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  • 151.
    Lagerlund, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed.

    A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS.

    A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized.

    The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.

    Delarbeten
    1. Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
    Öppna denna publikation i ny flik eller fönster >>Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
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    2007 (Engelska)Ingår i: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 10, nr 9, s. 783-789Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A microwave-enhanced, palladium-catalyzed protocol for the alpha-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity.

    Nyckelord
    arylation, glutamine synthetase, microwave, palladium, tuberculosis, water
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-16614 (URN)10.2174/138620707783018478 (DOI)000253584600005 ()18478959 (PubMedID)
    Tillgänglig från: 2008-06-05 Skapad: 2008-06-05 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
    Öppna denna publikation i ny flik eller fönster >>Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
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    2009 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, nr 16, s. 4790-4793Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.

    Nyckelord
    Mycobacterium tuberculosis, Glutamine synthetase inhibitors, Microwave, 3-Aminoimidazo[1, 2-a]pyridine
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-100360 (URN)10.1016/j.bmcl.2009.06.045 (DOI)000268358800057 ()19560924 (PubMedID)
    Tillgänglig från: 2009-03-31 Skapad: 2009-03-31 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    3. Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
    Öppna denna publikation i ny flik eller fönster >>Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
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    2012 (Engelska)Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, nr 5, s. 620-626Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

    Nationell ämneskategori
    Läkemedelskemi Medicin och hälsovetenskap
    Forskningsämne
    Kemi med inriktning mot organisk kemi; Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-100359 (URN)10.1039/c2md00310d (DOI)000304387300013 ()
    Tillgänglig från: 2009-03-31 Skapad: 2009-03-31 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    4. Microwave-promoted aminocarbonylations of aryl chlorides using Mo(CO)(6) as a solid carbon monoxide source.
    Öppna denna publikation i ny flik eller fönster >>Microwave-promoted aminocarbonylations of aryl chlorides using Mo(CO)(6) as a solid carbon monoxide source.
    2005 (Engelska)Ingår i: J Comb Chem, ISSN 1520-4766, Vol. 8, nr 1, s. 4-6Artikel i tidskrift (Refereegranskat) Published
    Nyckelord
    Benzamides/*chemical synthesis/chemistry, Benzene Derivatives/*chemistry, Carbon Monoxide/*chemistry, Catalysis, Combinatorial Chemistry Techniques, Hydrocarbons; Chlorinated/*chemistry, Microwaves, Molecular Structure, Molybdenum/*chemistry, Palladium/chemistry, Research Support; Non-U.S. Gov't
    Identifikatorer
    urn:nbn:se:uu:diva-75624 (URN)16398545 (PubMedID)
    Tillgänglig från: 2006-02-13 Skapad: 2006-02-13 Senast uppdaterad: 2011-01-11
    5. Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
    Öppna denna publikation i ny flik eller fönster >>Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
    2009 (Engelska)Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, nr 36, s. 7646-7652Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of alkenyl chlorides, bromides, and triflates were investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded moderate to good yields producing a wide variety of acrylamides after 20 minutes of microwave irradiation. In addition, the aminocarbonylation reaction was, for the first time, expanded to include alkenyl phosphates as starting materials.

    Nyckelord
    Carbonylation, Microwave, Vinyl halides, Vinyl phosphates, Vinyl triflates, Alkenyl electrophiles, Palladium, Enolizable ketones
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-100358 (URN)10.1016/j.tet.2009.06.101 (DOI)000269340000043 ()
    Tillgänglig från: 2009-03-31 Skapad: 2009-03-31 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 152.
    Lagerlund, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mantel, Mette L. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source2009Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, nr 36, s. 7646-7652Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of alkenyl chlorides, bromides, and triflates were investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded moderate to good yields producing a wide variety of acrylamides after 20 minutes of microwave irradiation. In addition, the aminocarbonylation reaction was, for the first time, expanded to include alkenyl phosphates as starting materials.

  • 153. Lam, V. M.
    et al.
    Rodriguez, D.
    Zhang, T.
    Koh, E. J.
    Carlsson, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salahpour, A.
    Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model2015Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 6, s. 2216-2223Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trace Amines (TA) are side-products of the synthesis of classical neurotransmitters within the brain. TAs exert their effect by binding to a family of G protein-coupled receptors termed Trace Amine-Associated Receptors (TAARs). TAAR1 is the best characterised member of this family and studies on TAAR1 have shown that this receptor is a negative regulator of dopamine transmission. Considering the limited number of pharmacological probes available for TAAR1, we aimed to identify novel ligands of this receptor using structure-based virtual screening. A homology model of TAAR1 was generated and over three million commercially available compounds were screened against the orthosteric site using molecular docking. Among the 42 top-ranked compounds that were tested in functional assays, three partial agonists with EC50 values ranging from 1 to 52 [small mu ]M were discovered. In addition, four potentially weak antagonists were identified. Ten analogs of the two most potent agonists from the screen were also evaluated and three of these displayed equal or greater activity compared to the parent compound. Several of the discovered ligands represent novel scaffolds and are thus promising starting points for development of new pharmacological tools for studying TAAR1 biology.

  • 154.
    Lampa, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease.

    The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.

    Delarbeten
    1. Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
    Öppna denna publikation i ny flik eller fönster >>Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
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    2008 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 6, s. 2955-2967Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P-1 moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.

    Nyckelord
    HCV, NS3, protease inhibitor, carbonylation, acyl sulfonamide, palladium
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95748 (URN)10.1016/j.bmc.2007.12.041 (DOI)000255127700023 ()18194867 (PubMedID)
    Tillgänglig från: 2007-04-13 Skapad: 2007-04-13 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
    Öppna denna publikation i ny flik eller fönster >>Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
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    2010 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, nr 14, s. 5413-5424Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.

    Nyckelord
    HCV, Protease inhibitors, Peptidomimetics, Phenylglycine, Resistance, Alkenylic acylsulfonamides
    Nationell ämneskategori
    Naturvetenskap Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-129431 (URN)10.1016/j.bmc.2010.05.027 (DOI)000279744700060 ()20541424 (PubMedID)
    Tillgänglig från: 2010-08-15 Skapad: 2010-08-15 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
    Öppna denna publikation i ny flik eller fönster >>P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
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    2011 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, nr 16, s. 4917-4927Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.

    Nyckelord
    HCV, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-157240 (URN)10.1016/j.bmc.2011.06.064 (DOI)000293503000025 ()
    Tillgänglig från: 2011-08-31 Skapad: 2011-08-22 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
    Öppna denna publikation i ny flik eller fönster >>Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-163354 (URN)
    Tillgänglig från: 2011-12-11 Skapad: 2011-12-11 Senast uppdaterad: 2012-01-16
    5. Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
    Öppna denna publikation i ny flik eller fönster >>Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-163356 (URN)
    Tillgänglig från: 2011-12-11 Skapad: 2011-12-11 Senast uppdaterad: 2012-01-16
  • 155.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ehrenberg, Angelica E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles2014Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, nr 23, s. 6595-6615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

  • 156.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Bergman, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ehrenberg, Angelica E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ RegionManuskript (preprint) (Övrigt vetenskapligt)
  • 157.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Bergman, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svahn Gustafsson, Sofia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Novel peptidomimetic HCV NS3 protease inhibitors spanning the P2-P1´ regionManuskript (preprint) (Övrigt vetenskapligt)
  • 158.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Bergman, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svahn Gustafsson, Sofia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Danielsson, Helena U.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region2014Ingår i: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, nr 3, s. 249-254Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

  • 159.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ehrenberg, Angelica E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Biokemi.
    Gustafsson, Sofia S.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Biokemi.
    Vema, Aparna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Biokemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents2010Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, nr 14, s. 5413-5424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.

  • 160.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ehrenberg, Angelica E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Vema, Aparna
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis2011Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, nr 16, s. 4917-4927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.

  • 161.
    Lampa, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Grandin, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ehrenberg, Angelica E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moietyManuskript (preprint) (Övrigt vetenskapligt)
  • 162.
    LARHED, M
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    ANDERSSON, CM
    HALLBERG, A
    CHELATION-CONTROLLED, PALLADIUM-CATALYZED ARYLATION OF ENOL ETHERS WITH ARYL TRIFLATES - LIGAND CONTROL OF SELECTION FOR ALPHA-ARYLATION OR BETA-ARYLATION OF [2-(DIMETHYLAMINO)ETHOXY]ETHENE1994Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 50, nr 2, s. 285-304Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Palladium-catalyzed arylation reactions of [2-(Dimethylamino)ethoxy]ethene (1) with a series of aryl triflates were performed under a variety of reaction conditions. In particular, the influence of phosphine ligands and halide additives on regioselectivity were studied. It was found that the chelation-controlled arylation of 1 affords an expedient route for the conversion of phenols into arylacetaldehydes. Alternatively, the same starting materials could be used to synthesize acetophenones by reversing the regioselectivity with bidentate phosphine ligands.

  • 163. Lauer, Dilyara
    et al.
    Slavic, Svetlana
    Sommerfeld, Manuela
    Thoene-Reineke, Christa
    Sharkovska, Yuliya
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Dahloef, Bjorn
    Kintscher, Ulrich
    Unger, Thomas
    Steckelings, Ulrike Muscha
    Kaschina, Elena
    AT2 Receptor Agonism Regulates TIMP1/MMP9 Axis in the Heart Preventing Cardiac Fibrosis and Improving Heart Function After Experimental Myocardial Infarction2013Ingår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, nr 3Artikel i tidskrift (Övrigt vetenskapligt)
  • 164. Lauer, Dilyara
    et al.
    Slavic, Svetlana
    Sommerfeld, Manuela
    Thoene-Reineke, Christa
    Sharkovska, Yuliya
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Dahlof, Bjorn
    Kintscher, Ulrich
    Unger, Thomas
    Steckelings, Ulrike Muscha
    Kaschina, Elena
    Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor beta 1 in the Rat Heart2014Ingår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, nr 3, s. E60-E67Artikel i tidskrift (Refereegranskat)
  • 165.
    Lazorova, Lucia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hubatsch, Ina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ekegren, Jenny K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gising, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nakai, Daisuke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Zaki, Noha M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Norinder, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Structural Features Determining the Intestinal Epithelial Permeability and Efflux of Novel HIV-1 Protease Inhibitors2011Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, nr 9, s. 3763-3772Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.

  • 166. Leblanc, Samuel
    et al.
    Battista, Marie-Claude
    Noll, Christophe
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gallo-Payet, Nicole
    Carpentier, Andre C.
    Vine, Donna F.
    Baillargeon, Jean-Patrice
    Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome2014Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, nr 9, s. 3684-3693Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 mu U/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g.min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km(P = .009), which were strongly correlated together in all PCOS/cp rats (rho = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

  • 167. Lehmann, Fredrik
    et al.
    Koolmeister, Tobias
    Odell, Luke R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Scobie, Martin
    A versatile new synthetic route to 1N-hydroxyindazoles2009Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, nr 21, s. 5078-5081Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new and versatile cyclization reaction affording rare 1N-hydroxyindazoles is presented. Treatment of 2-nitrobenzylamines with methanolic sodium hydroxide furnishes 1N-hydroxyindazoles regioselectively and in high yield. The reaction tolerates a range of functional groups and electronic effects.

  • 168.
    Lindberg, Jimmy
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Pyring, David
    Löwgren, Seved
    Rosenquist, Åsa
    Zuccarello, Guido
    Kvarnström, Ingemar
    Zhang, Hong
    Vrang, Lotta
    Classon, Björn
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Symmetric fluoro-substituted diol-based HIV protease inhibitors: Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy2004Ingår i: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 271, nr 22, s. 4594-4602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 A resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluoro-substitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

  • 169.
    Lindh, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium(II)-Catalyzed Coupling Reactions2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II).

    The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed.

    In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established.

    A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed.

    In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained.

    The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested.

    Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.

    Delarbeten
    1. Open-air oxidative Heck reactions at room temperature
    Öppna denna publikation i ny flik eller fönster >>Open-air oxidative Heck reactions at room temperature
    2006 (Engelska)Ingår i: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 8, nr 4, s. 338-343Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Palladium(II)-catalyzed oxidative Heck arylation reactions proceed at room temperature with atmospheric air as the sole reoxidant. Using arylboronic acids as arylating agents and inexpensive 2,9-dimethyl-1,10-phenanthroline as the supporting ligand, efficient vinylic substitution reactions were obtained both with electron-poor and electron-rich olefins on a 1–50 mmol scale.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-94792 (URN)10.1039/B517152K (DOI)
    Tillgänglig från: 2006-09-14 Skapad: 2006-09-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
    Öppna denna publikation i ny flik eller fönster >>Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
    Visa övriga...
    2007 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 21, s. 7957-7962Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Scope and limitations of the base-free oxidative Heck reaction with arylboronic acids have been explored. Under our conditions, the dmphen−palladium(II)-catalyzed arylation proceeded with air or p-benzoquinone as reoxidants of palladium(0). We found that ambient temperature and mild aerobic conditions allow for the use of substrates sensitive to palladium(II)-catalyzed oxidation. Oxidative Heck couplings, employing different arylboronic acids, were smoothly and regioselectively conducted with both electron-rich and electron-poor olefins, providing high yields even with disubstituted butyl methacrylate, sensitive acrolein, and a vinylboronate ester. Controlled microwave processing was used to reduce reaction times from hours to minutes both in small scale and in 50 mmol scale batch processes.

    Nyckelord
    Acrylates/*chemistry, Aerobiosis, Benzene Derivatives/*chemistry, Boronic Acids/*chemistry, Catalysis, Chemistry; Organic/*methods, Heat, Microwaves, Oxidation-Reduction, Palladium/*chemistry, Temperature
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-16615 (URN)10.1021/jo701434s (DOI)000249986500019 ()17887706 (PubMedID)
    Tillgänglig från: 2008-05-29 Skapad: 2008-05-29 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Öppna denna publikation i ny flik eller fönster >>Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Visa övriga...
    2009 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 18, s. 4630-4636Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

    Nyckelord
    Heck reaction, mass spectrometry, mechanistic studies, palladium, styrene
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-102918 (URN)10.1002/chem.200802744 (DOI)000265955200018 ()19274694 (PubMedID)
    Tillgänglig från: 2009-05-13 Skapad: 2009-05-12 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
    Öppna denna publikation i ny flik eller fönster >>Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
    2010 (Engelska)Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 12, s. 2270-2274Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

    Nyckelord
    Continuous flow, cross-coupling, Boron, Palladium, homogeneous catalysis, organic-synthesis, base-free, coupling reactions, room-temperature, bond formation, efficient, catalysis, palladium, air, perspective
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-130028 (URN)10.1002/ejoc.201000063 (DOI)000277332500004 ()
    Tillgänglig från: 2010-08-27 Skapad: 2010-08-27 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    5. Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
    Öppna denna publikation i ny flik eller fönster >>Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
    Visa övriga...
    2009 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 47, s. 13069-13074Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The first Pd-II-catalyzed P arylation has been performed by using palladium acetate, the rigid bidentate ligand dmphen (dmphen=2,9-dimethyl-1,10-phenanthroline), and without the addition of base or acid. Couplings of arylboronic acids or aryl trifluoroborates with H-phosphonate dialkyl esters were conducted in 30 min with controlled microwave (MW) heating under non-inert conditions. Aryl phosphites were also synthesized at room temperature with atmospheric air as the sole reoxidant. The arylated phosphonates were isolated in 44-90% yields. The excellent chemoselectivity of the method was illustrated in the synthesis of a Mycobacterium tuberculosis glutamine synthetase (MTB-GS) inhibitor. Online ESIMS was used to detect cationic palladium species in ongoing reactions directly, and a catalytic cycle has been proposed based on these results.

    Ort, förlag, år, upplaga, sidor
    Weinheim: Wiley-VCH Verlag GmbH, 2009
    Nyckelord
    Boronic acids, microwave chemistry, palladium, P arylation, trifluoroborates
    Nationell ämneskategori
    Analytisk kemi
    Forskningsämne
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-113919 (URN)10.1002/chem.200901473 (DOI)000273697100021 ()19856344 (PubMedID)
    Tillgänglig från: 2010-02-04 Skapad: 2010-02-04 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    6.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
  • 170.
    Lindh, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fardost, Ashkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Almeida, Maria
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Convenient Stille carbonylative cross-couplings using molybdenum hexacarbonyl2010Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 18, s. 2470-2472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Palladium catalysis was used in Stille-type carbonylative cross-couplings employing Mo(CO)(6) as the carbon monoxide source. Robust and convenient transformations were carried out in closed vessels at 100 degrees C, providing a set of diaryl ketones in good yields. Aryl triflates and bromides were used as coupling partners with aryl stannanes. Inclusion of the Mo(CO)(6) destabilizing agent DBU made this protocol operationally simple and suppressed side-product formation. (C) 2010 Elsevier Ltd. All rights reserved.

  • 171.
    Lindh, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Microwave-assisted palladium(II)-catalyzed Heck reactions2009Ingår i: Chimica oggi, ISSN 0392-839X, E-ISSN 1973-8250, Vol. 27, nr 2, s. 11-14Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During the last couple of years we have reported on a number of microwave promoted oxidative Heck reactions with the aim of developing efficient and environmentally benign procedures. The use of microwave irradiation has enabled us to drastically improve reaction rates and to use substrates which are virtually unreactive at lower temperatures. A few multi-gram scale batch reactions have also been successfully executed. Several different oxidants for regeneration of palladium(II) have been evaluated from which air is the most attractive due to its low-cost, ease-of-use and low environmental impact. The use of air as palladium reoxidant was made possible by employing bidentate nitrogen ligands.

  • 172.
    Lindh, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. ORGFARM.
    Sjöberg, Per J. R.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of aryl ketones by palladium(II)-catalyzed decarboxylative addition of benzoic acids to nitriles2010Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 49, nr 42, s. 7733-7737Artikel i tidskrift (Refereegranskat)
  • 173.
    Lindh, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    Sjöberg, Per J R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate2009Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 18, s. 4630-4636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

  • 174.
    Lindh, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Computational Modelling in Drug Discovery: Application of Structure-Based Drug Design, Conformal Prediction and Evaluation of Virtual Screening2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Structure-based drug design and virtual screening are areas of computational medicinal chemistry that use 3D models of target proteins. It is important to develop better methods in this field with the aim of increasing the speed and quality of early stage drug discovery.

    The first part of this thesis focuses on the application of structure-based drug design in the search for inhibitors for the protein 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), one of the enzymes in the DOXP/MEP synthetic pathway. This pathway is found in many bacteria (such as Mycobacterium tuberculosis) and in the parasite Plasmodium falciparum.

    In order to evaluate and improve current virtual screening methods, a benchmarking data set was constructed using publically available high-throughput screening data. The exercise highlighted a number of problems with current data sets as well as with the use of publically available high-throughput screening data. We hope this work will help guide further development of well designed benchmarking data sets for virtual screening methods.

    Conformal prediction is a new method in the computer-aided drug design toolbox that gives the prediction range at a specified level of confidence for each compound. To demonstrate the versatility and applicability of this method we derived models of skin permeability using two different machine learning methods; random forest and support vector machines.

    Delarbeten
    1. Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
    Öppna denna publikation i ny flik eller fönster >>Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
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    2011 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 14, s. 4964-4976Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

    Nationell ämneskategori
    Biokemi och molekylärbiologi Annan medicinsk grundvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-156614 (URN)10.1021/jm2000085 (DOI)000292892300003 ()21678907 (PubMedID)
    Tillgänglig från: 2011-08-07 Skapad: 2011-08-04 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: An attempt to improve the activity against Mycobacterium tuberculosis
    Öppna denna publikation i ny flik eller fönster >>Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: An attempt to improve the activity against Mycobacterium tuberculosis
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    2011 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, nr 18, s. 5403-5407Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Two series of FR900098/fosmidomycin analogs were synthesized and evaluated for MtDXR inhibition and Mycobacterium tuberculosis whole-cell activity. The design rationale of these compounds involved the exchange of either the phosphonic acid or the hydroxamic acid part for alternative acidic and metal-coordinating functionalities. The best inhibitors provided IC(50) values in the micromolar range, with a best value of 41 mu M.

    Nyckelord
    Tuberculosis, DXR, Enzyme inhibitor, Fosmidomycin, FR900098
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-158288 (URN)10.1016/j.bmcl.2011.07.005 (DOI)000294051800057 ()
    Tillgänglig från: 2011-09-07 Skapad: 2011-09-06 Senast uppdaterad: 2017-12-08
    3. DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
    Öppna denna publikation i ny flik eller fönster >>DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
    Visa övriga...
    2013 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, nr 15, s. 6190-6199Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.

    Nyckelord
    Mycobacterium tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR
    Nationell ämneskategori
    Strukturbiologi
    Forskningsämne
    Biologi med inriktning mot strukturbiologi; Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-196616 (URN)10.1021/jm4006498 (DOI)000323082400015 ()
    Forskningsfinansiär
    Stiftelsen för strategisk forskning (SSF)Vetenskapsrådet
    Anmärkning

    De tre (3) första författarna delar förstaförfattarskapet.

    Tillgänglig från: 2013-03-11 Skapad: 2013-03-11 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    4. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Öppna denna publikation i ny flik eller fönster >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Visa övriga...
    2015 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, nr 2, s. 343-353Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2015
    Nationell ämneskategori
    Strukturbiologi Farmaceutisk synteskemi
    Forskningsämne
    Kemi med inriktning mot bioorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Tillgänglig från: 2015-03-26 Skapad: 2015-03-26 Senast uppdaterad: 2018-03-05Bibliografiskt granskad
    5. Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework
    Öppna denna publikation i ny flik eller fönster >>Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework
    2017 (Engelska)Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 5, s. 1571-1576Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

    Nyckelord
    conformal prediction, skin penetration nonconformist, Scikit Learn, random forest, Support vector machines
    Nationell ämneskategori
    Medicinska och farmaceutiska grundvetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-323448 (URN)10.1021/acs.molpharmaceut.7b00007 (DOI)000400633300024 ()28335598 (PubMedID)
    Tillgänglig från: 2017-07-04 Skapad: 2017-07-04 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 175.
    Lindh, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Norinder, Ulf
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, SE-15136 Sodertalje, Sweden.;Stockholm Univ, Dept Comp & Syst Sci, Forum 100, SE-16440 Kista, Sweden..
    Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework2017Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 5, s. 1571-1576Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

  • 176.
    Lindh, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Svensson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Zhang, Jin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data2015Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, nr 2, s. 343-353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

  • 177.
    Lindman, Susanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II2001Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 9, nr 3, s. 763-772Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclic 12-, 13- and 14-membered ring angiotensin II analogues related to disulfides but encompassing methylenedithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the disulfides. The methylenedithioether analogues displayed good binding affinities to rat liver AT1 receptors although in most cases somewhat lower than their disulfide counterparts. One of the methylenedithioethers with a 13-membered ring system demonstrated the highest binding affinity among the thioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and the corresponding methylenedithioether analogues and also between the ring size homologues. This analysis also suggested that some of the model compounds were prone to adopt inverse γ-turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in the series. The easily executed methylenedithioether cyclization should constitute a valuable complement to the common disulfide methodology for fine-tuning and for probing the bioactive conformation of peptides.

  • 178.
    Lubberink, Mark
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala Univ Hosp, Med Phys..
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala Univ Hosp, Med Imaging Ctr..
    Lindskog, K.
    Uppsala Univ Hosp, Med Phys..
    Danfors, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala Univ Hosp, Med Imaging Ctr..
    Sprycha, M.
    Uppsala Univ Hosp, Med Imaging Ctr..
    Daging, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Uppsala Univ Hosp, Neurol..
    Eriksson, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala Univ Hosp, Med Imaging Ctr..
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala Univ Hosp, Med Imaging Ctr..
    Kumlien, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi. Uppsala Univ Hosp, Neurol..
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala Univ Hosp, Med Imaging Ctr..
    Quantitative assessment of synaptic density using the SV2A ligand C-11-UCBA in humans2017Ingår i: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, s. 74-74Artikel i tidskrift (Övrigt vetenskapligt)
  • 179.
    Lundstedt, Torbjorn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Patnaik, Ranjana
    Patnaik, S
    Sharma, Aruna
    Lek, Per
    Seifert, Elisabeth
    Sharma, Shanker
    Nanodrug delivery in spinal cord injury alters neuronal and axonal proteins expression and enhances neurorepair: (Meeting Abstract)2009Ingår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 37, s. 25-26Artikel i tidskrift (Refereegranskat)
  • 180.
    Lundstedt, Torbjörn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Moritz, Tomas
    Umeå Universitet.
    Madsen, R
    Lundstedt-Enkel, Katrin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Trygg, Johan
    Umeå Universitet.
    Endogenous metabolic profiling as a tool in drug discovery2010Ingår i: 7th Annual Global Conference on Neuroprotection and Neuroregeneration: Radisson Blu Arlandia Hotel 28 February-3 March, 2010 : abstract book, 2010, s. 25-Konferensbidrag (Övrigt vetenskapligt)
  • 181. Macsari, Istvan
    et al.
    Besidski, Yeygeni
    Csjernyik, Gabor
    Nilsson, Linda I.
    Sandberg, Lars
    Yngve, Ulrika
    Ahlin, Kristofer
    Bueters, Tjerk
    Eriksson, Anders B.
    Lund, Per-Eric
    Venyike, Elisabet
    Oerther, Sandra
    Blakeman, Karin Hygge
    Luo, Lei
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models2012Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 15, s. 6866-6880Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

  • 182. Macsari, Istvan
    et al.
    Sandberg, Lars
    Besidski, Yevgeni
    Gravenfors, Ylva
    Ginman, Tobias
    Bylund, Johan
    Bueters, Tjerk
    Eriksson, Anders B.
    Lund, Per-Eric
    Venyike, Elisabet
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship2011Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, nr 13, s. 3871-3876Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.

  • 183. Madsen, Rasmus K.
    et al.
    Lundstedt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gabrielsson, Jon
    Sennbro, Carl-Johan
    Alenius, Gerd-Marie
    Moritz, Thomas
    Rantapää-Dahlqvist, Solbritt
    Trygg, Johan
    Diagnostic properties of metabolic perturbations in rheumatoid arthritis2011Ingår i: Arthritis Research and Therapy, ISSN 1478-6354, Vol. 13, nr 1, s. R19-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The aim of this study was to assess the feasibility of diagnosing early rheumatoid arthritis (RA) by measuring selected metabolic biomarkers. Methods: We compared the metabolic profile of patients with RA with that of healthy controls and patients with psoriatic arthritis (PsoA). The metabolites were measured using two different chromatography-mass spectrometry platforms, thereby giving a broad overview of serum metabolites. The metabolic profiles of patient and control groups were compared using multivariate statistical analysis. The findings were validated in a follow-up study of RA patients and healthy volunteers. Results: RA patients were diagnosed with a sensitivity of 93% and a specificity of 70% in a validation study using detection of 52 metabolites. Patients with RA or PsoA could be distinguished with a sensitivity of 90% and a specificity of 94%. Glyceric acid, D-ribofuranose and hypoxanthine were increased in RA patients, whereas histidine, threonic acid, methionine, cholesterol, asparagine and threonine were all decreased compared with healthy controls. Conclusions: Metabolite profiling (metabolomics) is a potentially useful technique for diagnosing RA. The predictive value was without regard to the presence of antibodies against cyclic citrullinated peptides.

  • 184. Madsen, Rasmus
    et al.
    Lundstedt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Trygg, Johan
    Chemometrics in metabolomics: a review in human disease diagnosis2010Ingår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 659, nr 1-2, s. 23-33Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Metabolomics is a post genomic research field concerned with developing methods for analysis of low molecular weight compounds in biological systems, such as cells, organs or organisms. Analyzing metabolic differences between unperturbed and perturbed systems, such as healthy volunteers and patients with a disease, can lead to insights into the underlying pathology. In metabolomics analysis, large amounts of data are routinely produced in order to characterize samples. The use of multivariate data analysis techniques and chemometrics is a commonly used strategy for obtaining reliable results. Metabolomics have been applied in different fields such as disease diagnosis, toxicology, plant science and pharmaceutical and environmental research. In this review we take a closer look at the chemometric methods used and the available results within the field of disease diagnosis. We will first present some current strategies for performing metabolomics studies, especially regarding disease diagnosis. The main focus will be on data analysis strategies and validation of multivariate models, since there are many pitfalls in this regard. Further, we highlight the most interesting metabolomics publications and discuss these in detail; additional studies are mentioned as a reference for the interested reader. A general trend is an increased focus on biological interpretation rather than merely the ability to classify samples. In the conclusions, the general trends and some recommendations for improving metabolomics data analysis are provided.

  • 185.
    Mahalingam, A. Kannan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Axelsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ekegren, Jenny K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wannberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Kihlström, Jacob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturell molekylärbiologi.
    Wallberg, Hans
    Samuelsson, Bertil
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 2, s. 607-615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

  • 186. Makatini, Maya M.
    et al.
    Petzold, Katja
    Alves, Claudio Nahum
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Honarparvar, Bahareh
    Govender, Patrick
    Govender, Thavendran
    Kruger, Hendrik G.
    Sayed, Yasien
    Lameira, Jeronimo
    Maguire, Glenn E. M.
    Soliman, Mahmoud E. S.
    Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors2013Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 28, nr 1, s. 78-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 mu M against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50 (0.5 mu M), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5-10 mu M). The PCU-peptides and peptoides were several orders less toxic (145 mu M for 11 and 102 mu M for 11 peptoid) to human MT-4 cells than lopinavir (0.025 mu M). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.

  • 187. Makatini, Maya M.
    et al.
    Petzold, Katja
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Honarparvar, Bahareh
    Govender, Thavendran
    Maguire, Glenn E. M.
    Parboosing, Raveen
    Sayed, Yasien
    Soliman, Mahmoud E. S.
    Kruger, Hendrik G.
    Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors2012Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 57, s. 459-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC50 values ranging from 6.5 to 0.075 mu M. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25' residues were observed from the docking and along the MD trajectories.

  • 188. Makatini, Maya M.
    et al.
    Petzold, Katja
    Sriharsha, Shimoga N.
    Ndlovu, N.
    Soliman, Mahmoud E. S.
    Honarparvar, Bahareh
    Parboosing, Raveen
    Naidoo, Anneta
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sayed, Yasien
    Govender, Patrick
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Govender, Thavendran
    Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach2011Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, nr 9, s. 3976-3985Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.

  • 189. Makatini, Maya M.
    et al.
    Petzold, Katja
    Sriharsha, Shimoga N.
    Soliman, Mahmoud E. S.
    Honarparvar, Bahareh
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sayed, Yasien
    Govender, Patrick
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Govender, Thavendran
    Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease2011Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, nr 8, s. 2274-2277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC50 activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.

  • 190. Maldonado, Matias Funes
    et al.
    Sehgelmeble, Fernando
    Bjarnemark, Fanny
    Svensson, Mats
    Ahman, Jens
    Arvidsson, Per I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis and arylation of unprotected sulfonimidamides2012Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, nr 36, s. 7456-7462Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein we evaluate different methodologies for the synthesis of unprotected sulfonimidamides. Three different procedures that allow orthogonal deprotection of the imine nitrogen under acidic, nucleophilic, and basic conditions were established. Moreover, we present a highly efficient methodology for functionalization of the imine nitrogen through Pd-catalyzed C-N arylation. RuPhos ligand was shown to allow short reaction time, excellent yields, and allowed coupling of both aryl halides and heteroaryl bromides.

  • 191.
    Malm, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Farnegardh, Mathias
    Grover, Gary J
    Ladenson, Paul W
    Thyroid Hormone Antagonists: Potential Medical Applications and Structure Activity Relationships2009Ingår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, nr 25, s. 3258-3266Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T-3, 1) and 3,5,3',5'-tetraiodo-L-thyronine (L-T-4, 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TR alpha-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix ( helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.

  • 192.
    Malm, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Grover, Gary J
    Thyroid hormons and thyromimetics2010Ingår i: Burger's Medicinal Chemistry, Drug Discovery and Development / [ed] Donald J. Abraham, David P. Rotella, John Wiley and Sons , 2010, 7, , s. 50s. 189-237Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    This chapter will provide an overview on the recent design principles and structure–activity relationship of thyroid hormones and thyromimetics. The prospects for the treatment of metabolic diseases, hypo- and hyperthyroidism, and cardiac disease with pharmacologically selective thyromimetics are considerable if cardiovascular acceleration and other adverse events can be avoided.

  • 193.
    Mane, Rajendra S
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide2013Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, nr 50, s. 6912-6915Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

  • 194. Martin, F. P. J.
    et al.
    Wang, Y.
    Sprenger, N.
    Yap, I. K. S.
    Lundstedt, T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lek, P.
    Rezzi, S.
    Ramadan, Z.
    van Bladeren, P.
    Fay, L. B.
    Kochhar, S.
    Lindon, J. C.
    Holmes, E.
    Nicholson, J. K.
    Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model2008Ingår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 4, s. 157-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.

  • 195. McCarthy, Claudia A.
    et al.
    Vinh, Antony
    Miller, Alyson A.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Alterman, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Callaway, Jennifer K.
    Widdop, Robert E.
    Direct Angiotensin AT2 Receptor Stimulation Using a Novel AT2 Receptor Agonist, Compound 21, Evokes Neuroprotection in Conscious Hypertensive Rats2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 4, s. e95762-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Methods and Results: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. Conclusion: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development.

  • 196.
    Mitran, Bogdan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Thisgaard, Helge
    Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine; University of Southern Denmark, Department of Clinical Research.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Dam, Johan Hygum
    Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM262017Ingår i: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, artikel-id UNSP 6873684Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

  • 197.
    Mitran, Bogdan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Development of radiocobalt-labeled GRPR antagonist NOTA-PEG2-RM26.2015Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, nr S1, s. S142-S142Artikel i tidskrift (Övrigt vetenskapligt)
  • 198.
    Mitran, Bogdan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Influence of chelators on biodistribution and targeting properties of GRPR antagonist2014Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, nr S2, s. S320-S320, artikel-id PW012Artikel i tidskrift (Övrigt vetenskapligt)
  • 199.
    Mitran, Bogdan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.2016Ingår i: International journal of oncology, ISSN 1791-2423, Vol. 48, nr 5, s. 2124-2134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the 111In-labeled bombesin antagonist PEG2-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (PEG2-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG2 spacer were radiolabeled with 111In and evaluated both in vitro and in vivo. The conjugates were successfully labeled with 111In with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged natIn-NOTA-PEG2-RM26 (2.6±0.1 nM) and higher values for negatively charged natIn-DOTAGA-PEG2-RM26 (4.8±0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 h p.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA- and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. 111In-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 h p.i., DOTA- and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA- and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 h p.i., had the highest contrast to blood, muscle and bones.

  • 200. Mohell, N.
    et al.
    Alfredsson, J.
    Fransson, A.
    Uustalu, M.
    Bystrom, S.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Bykov, V. J. N.
    Bjorklund, U.
    Wiman, K. G.
    APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells2015Ingår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, artikel-id e1794Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wildtype conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

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