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  • 1. Alogheli, H.
    et al.
    Belfrage, A. K.
    Lampa, A.
    Gising, J.
    Åkerblom, E.
    Danielson, H.
    Sandstrom, A.
    Karlen, A.
    Binding mode prediction of HCV NS3A protease inhibitors2012Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 244Artikel i tidskrift (Refereegranskat)
  • 2. Antonov, D
    et al.
    Ayesa Alvarez, S
    Belfrage,, Anna Karin G. L.
    Jönsson, C.E.D.
    Mcgowan, D.C.
    Nilsson, K. M.
    Raboisson, P. J
    Rosenquist,, Å. A. K.
    Samuelsson,, B.B.
    HCV inhibiting macrocyclic phenylcarbamates2008Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Compounds of the formula I: including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.

  • 3. Ayesa, S.
    et al.
    Belfrage, Anna Karin
    Classon, B.
    Grabowska, U.
    Hewitt, E.
    Ivanov, V.
    Jönsson, D.
    Kahnberg, P.
    Lind, P.
    Nilsson, M.
    Odén, L.
    Pelcman, M.
    Wähling, H.
    CYSTEINE PROTEASE INHIBITORS2011Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Compounds of the formula I

    wherein

    R1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; or

    R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms;

    R2a and R2b are H, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy; or

    R2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl;

    R3 is a branched C5-C10alkyl chain, C2-C4haloalkyl or C3-C7cycloalkylmethyl,

    R4 is Het, Carbocyclyl,

    optionally substituted as defined in the specification and pharmaceutically acceptable salts,

    hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain.

  • 4. Belfrage, A. K.
    et al.
    Gising, J.
    Örtqvist, P.
    Danielson, U. H.
    Larhed, M.
    Sandström, A.
    Hepatitis C Virus NS3 Protease Inhibitors based on 2(1H)-Pyrazinones2010Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 16, s. 95-95Artikel i tidskrift (Refereegranskat)
  • 5.
    Belfrage, Anna Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.

    The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.

    Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

    Delarbeten
    1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Öppna denna publikation i ny flik eller fönster >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Visa övriga...
    2010 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, nr 14, s. 4004-4011Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

    Nyckelord
    HCV, NS3/4A protease, Inhibitors, P2 substituent, Quinazoline, Replicon assay, In vitro, DMPK, In vivo PK
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-136039 (URN)10.1016/j.bmcl.2010.05.029 (DOI)000279258800001 ()
    Tillgänglig från: 2010-12-09 Skapad: 2010-12-09 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
    Öppna denna publikation i ny flik eller fönster >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
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    2014 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, nr 5, s. 1790-1801Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
    Tillgänglig från: 2012-03-31 Skapad: 2012-03-31 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Öppna denna publikation i ny flik eller fönster >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Visa övriga...
    2016 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, nr 12, s. 2603-2620Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Nyckelord
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, D0571301
    Tillgänglig från: 2015-02-08 Skapad: 2015-02-08 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
    4. Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
    Öppna denna publikation i ny flik eller fönster >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
    Visa övriga...
    2015 (Engelska)Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 5, s. 978-986Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Kemi med inriktning mot organisk kemi; Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
    Tillgänglig från: 2015-02-06 Skapad: 2015-02-06 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
    5. Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    Öppna denna publikation i ny flik eller fönster >>Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    palladium
    Nationell ämneskategori
    Organisk kemi
    Forskningsämne
    Läkemedelskemi; Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-243257 (URN)
    Tillgänglig från: 2015-02-06 Skapad: 2015-02-06 Senast uppdaterad: 2015-03-11
  • 6.
    Belfrage, Anna Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Synthesis and SAR around the R6 Position of 2(1H)-Pyrazinone Based Hepatitis C (HCV) NS3 Protease Inhibitors2011Proceedings (redaktörskap) (Refereegranskat)
  • 7.
    Belfrage, Anna Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Abdurakhmanov, Eldar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Åkerblom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Neyts, Johan
    Rega Institute, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Johansson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold2018Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, s. 453-464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

  • 8.
    Belfrage, Anna Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Abdurakhmanov, Eldar
    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.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Oshalim, Anna
    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.
    Skogh, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Neyts, Johan
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease2016Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, nr 12, s. 2603-2620Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

  • 9.
    Belfrage, Anna Karin
    et al.
    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.
    Svensson, Fredrik
    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.
    Sköld, Christian
    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.
    Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones2015Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 5, s. 978-986Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

  • 10.
    Belfrage, Anna Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Wakchaure, Prasad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Palladium-Catalyzed Carbonylation of Aryl Iodides with Sulfinamides2015Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 32, s. 7069-7074Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A facile palladium(0)-catalyzed carbonylative protocol for the generation of new acyl-sulfinamides in moderate to good yields is described. Aliphatic and aromatic sulfinamides were exploited as hitherto unexplored nucleophiles in carbonylation chemistry, with use of CO gas generated ex situ from Mo(CO)6 in a sealed two-chamber system. Both electron-poor and electron-rich (hetero)aryl iodides were employed as electrophiles. The two-chamber system and the use of an inorganic base were essential for efficacious synthesis of acyl-sulfinamide products. Finally, it was demonstrated that a one-pot (or single-vial) synthesis of acyl-sulfinamides was feasible under CO at balloon pressure in the presence of Cs2CO3 as base.

  • 11.
    Gising, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Belfrage, Anna Karin
    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
    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.
    Anders, Karlén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielsson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Larhed, Mats
    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.
    Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket2014Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, nr 5, s. 1790-1801Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  • 12.
    Gising, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Belfrage, Anna Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Örtqvist, Pernilla
    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.
    Danielson, U. Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sandström, Anja
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Hepatitis C protease inhibitors based on 2(1H)-pyrazinones2010Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 240, s. 116-MEDI-Artikel i tidskrift (Refereegranskat)
  • 13. GISING, Johan
    et al.
    LINDSTRÖM, Stefan
    ANTONOV, Dmitry
    BRANDT, Peter
    BELFRAGE, Anna Karin
    BREM, Jürgen
    SCHOFIELD, Christopher J
    INHIBITORS OF METALLO-BETA-LACTAMASES: WO/2018/2158002018Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    The present invention relates to certain compounds that function as inhibitors of bacterial metallo-beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection.

  • 14. Johansson, Per-Ola
    et al.
    Chen, Yantao
    Belfrage, Anna Karin
    Blackman, Michael J
    Kvarnström, Ingemar
    Jansson, Katarina
    Vrang, Lotta
    Hamelink, Elizabeth
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Rosenquist, Asa
    Samuelsson, Bertil
    Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II: Use of solid-phase synthesis to explore novel statine motifs2004Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, nr 13, s. 3353-3366Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

  • 15. Nilsson, Magnus
    et al.
    Belfrage, Anna Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindstrom, Stefan
    Wahling, Horst
    Lindquist, Charlotta
    Ayesa, Susana
    Kahnberg, Pia
    Pelcman, Mikael
    Benkestock, Kurt
    Agback, Tatiana
    Vrang, Lotta
    Terelius, Ylva
    Wikstrom, Kristina
    Hamelink, Elizabeth
    Rydergard, Christina
    Edlund, Michael
    Eneroth, Anders
    Raboisson, Pierre
    Lin, Tse-I
    de Kock, Herman
    Wigerinck, Piet
    Simmen, Kenneth
    Samuelsson, Bertil
    Rosenquist, Asa
    Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents2010Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, nr 14, s. 4004-4011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

  • 16. Nilsson, Magnus
    et al.
    Kalayanov, Genadiy
    Winqvist, Anna
    Pinho, Pedro
    Sund, Christian
    Zhou, Xiao- Xiong
    Wahling, Horst
    Belfrage, Anna Karin
    Medivir AB, PO Box 1086, SE-141 22 Huddinge, Sweden.
    Pelcman, Michael
    Agback, Tatiana
    Benckestock, Kurt
    Wikström, Kristina
    Boothee, Mirva
    Lindqvist, Anneli
    Rydegard, Christina
    Jonckers, Tim H. M.
    Vandyck, Koen
    Raboisson, Pierre
    Lin, Tse-I
    Lachau-Durand, Sophie
    de Kock, Herman
    Smith, David B.
    Martin, Joseph A.
    Klumpp, Klaus
    Simmen, Kenneth
    Vrang, Lotta
    Terelius, Ylva
    Samuelsson, Bertil
    Rosenquist, Åsa
    Johansson, Nils Gunnar
    Discovery of 4 '-azido-2 '-deoxy-2 '-C-methyl cytidine and prodrugs thereof: A potent inhibitor of Hepatitis C virus replication2012Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 22, nr 9, s. 3265-3268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 value of 1.2 mu M and showing moderate in vivo bioavailability in rat (F = 14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof. (C) 2012 Elsevier Ltd. All rights reserved.

  • 17. RABOISSON, P. J. B.
    et al.
    BELFRAGE, Anna Karin G. L.
    CLASSON, B. O.
    LINDQUIST,, K. C.
    NILSSON, K. M.
    ROSENQUIST, Å. A. K.
    SAMUELSSON,, B. B.
    WÄHLING,, H. J.
    PYRIMIDINE SUBSTITUTED MACROCYCLIC HCV INHIBITORS2008Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Compounds of the Formula (I) including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.

  • 18. Simmen, K. A.
    et al.
    De Kock, H. A.
    Raboisson,, P. J.
    Hu, L.
    Tahri, A.
    Surleraux,, D. L. N. G.
    Nilsson, K. M.
    Samuelsson, B. B.
    Rosenquist, Å. A. K.
    Ivanov, V.
    Pelcman, M.
    Belfrage,, Anna Karin G. L.
    Johansson, P. M.
    Vendeville,, S. M. H.
    Macrocylic inhibitors of hepatitis C virus2012Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Inhibitors of HCV replication of formula (I)

    and the N-oxides, salts, and stereoisomers, wherein

    • each dashed line represents an optional double bond;
    • X is N, CH and where X bears a double bond it is C;
    • R1 is —OR7, —NH—SO2R8;
    • R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl;
    • R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl;
    • R4 is aryl or Het; n is 3, 4, 5, or 6;
    • R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het;
    • R6 is C1-6alkoxy, or dimethylamino;
    • R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;
    • R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;
    • aryl is phenyl optionally substituted with one, two or three substituents;
    • Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents;
    • pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
  • 19. Smith, M.
    et al.
    Martin, J.
    Smith, D.
    Maag, H.
    Naiera, I.
    Jiang, W. R.
    Klumpp, K.
    Leveque, V.
    Cammack, N.
    Johansson, N. G.
    Kalayanov, G.
    Belfrage, A. K.
    Benkestock, K.
    Farnell, K.
    Hiscock, S.
    Lindborg, B.
    Maltseva, T.
    Morisson, V.
    Pinho, P.
    Sund, C.
    Tozer, M.
    Winquist, A.
    Zhou, X. X.
    MEDI 236-Synthesis and anti-HCV activity of 4'-substituted nucleosides2006Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 232Artikel i tidskrift (Refereegranskat)
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