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  • 1.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor2017In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed)
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

  • 2.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

    List of papers
    1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Show others...
    2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91425 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Show others...
    2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91426 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, p. 2313-2324Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91427 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Show others...
    2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91428 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91429 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
    6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91430 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
  • 3.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fontaine, Fabien
    Karlén, Anders
    Andersson, Tommy B.
    Masimirembwa, Collen
    Pastor, Manuel
    Zamora, Ismael
    Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.Manuscript (Other academic)
  • 4.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Zamora, Ismael
    Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.2002In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed)
  • 5.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Raubacher, Florian
    Karlén, Anders
    Jørgensen, Flemming S.
    Andersson, Tommy B.
    Masimirembwa, Collen
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.Manuscript (Other academic)
  • 6.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Mecucci, Silvio
    Baroni, Massimo
    Cruciani, Gabriele
    A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed)
  • 7.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Ridderström, Marianne
    Andersson, Tommy B.
    Karlén, Anders
    Masimirembwa, Collen
    Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis2001In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed)
  • 8.
    Agalo, Faith
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Insulin-Regulated Aminopeptidase (IRAP) inhibitors2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory.

    IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier.

    Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies.

    IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development.

    The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues.

    Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

     

  • 9.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.

    Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.

    The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.

    Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.

    List of papers
    1. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
    Open this publication in new window or tab >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
    Show others...
    2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, p. 453-464Article in journal (Refereed) Published
    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).

    Place, publisher, year, edition, pages
    Elsevier, 2018
    Keywords
    Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
    Funder
    Swedish Research Council, D0571301
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-05-31Bibliographically approved
    2. A study of conformational energy penalties of protein-bound macrocycles
    Open this publication in new window or tab >>A study of conformational energy penalties of protein-bound macrocycles
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340863 (URN)
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-02-04
    3. Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    Open this publication in new window or tab >>Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-340864 (URN)
    Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-02-04
    4. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Open this publication in new window or tab >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Show others...
    2017 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed) Published
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
    Funder
    Swedish Research Council, 521-2014-6711
    Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-03-05Bibliographically approved
    5. Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
    Open this publication in new window or tab >>Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
    Show others...
    2014 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, no 23, p. 6595-6615Article in journal (Refereed) Published
    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.

    Keywords
    HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-239738 (URN)10.1016/j.bmc.2014.10.010 (DOI)000345287300007 ()
    Available from: 2014-12-31 Created: 2014-12-30 Last updated: 2018-02-04Bibliographically approved
    6. Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
    Open this publication in new window or tab >>Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
    Show others...
    2014 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 3, p. 249-254Article in journal, Letter (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-221229 (URN)10.1021/ml400217r (DOI)000333006200005 ()
    Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2018-02-04Bibliographically approved
  • 10.
    Alogheli, Hiba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olanders, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 11.
    Andaloussi, Mounir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Henriksson, Lena M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Wieckowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Björkelid, Christofer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Larsson, Anna M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Suresh, Surisetti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Iyer, Harini
    Srinivasa, Bachally R.
    Bergfors, Terese
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Mowbray, Sherry L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Jones, T. Alwyn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 14, p. 4964-4976Article in journal (Refereed)
    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.

  • 12.
    Andaloussi, Mounir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sjöberg, Per J.R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.2009In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 47, p. 13069-13074Article in journal (Refereed)
    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.

  • 13.
    Andaloussi, Mounir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Björkelid, Christofer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Suresh, Surisetti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wieckowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Iyer, Harini
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: An attempt to improve the activity against Mycobacterium tuberculosis2011In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, no 18, p. 5403-5407Article in journal (Refereed)
    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.

  • 14.
    Andappan, Murugaiah M. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mahalingam, A. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wan, Yiqian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Guimond, Marie-Odile
    Joshi, Advait
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 5, p. 2265-2278Article in journal (Refereed)
    Abstract [en]

    A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.

  • 15.
    Andappan, Murugaiah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Arylboronic acids as versatile coupling partners in fast microwave promoted oxidative Heck chemistry2003In: Molecular diversity, ISSN 1381-1991, E-ISSN 1573-501X, Vol. 7, no 2-4, p. 97-106Article in journal (Refereed)
    Abstract [en]

    The useful and selective reactivity of arylboronic acids makes them favourite building blocks for many modern organic chemistry applications like the metal-mediated formation of C-C, C-O, C-N, and C-S bonds. This report describes oxidative Heck coupling reactions of arylboronic acids and olefins, which were conveniently and rapidly (5-30 min) carried out under air with temperature-controlled microwave heating. Different reaction conditions were investigated with regard to both microwave heating capability and chemical productivity. Copper(II) acetate was identified as a microwave compatible reoxidant of Pd(0). The scope and limitations of this high-speed chemistry protocol with diverse olefins and organoboronic acids are discussed.

  • 16.
    Andersson Dunstan, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Liu, Boling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Welch, Christopher J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alphitol, a phenolic substance from Alphitonia zizyphoides which inhibits prostaglandin biosynthesis in vitro1998In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 48, no 3, p. 495-497Article in journal (Refereed)
    Abstract [en]

    The new phenolic compound, 3,5-dihydroxy-4-methoxy phenethyl alcohol, named alphitol, and betulinic acid were isolated from the bark of Alphitonia zizyphoides. The chemical structure of alphitol was determined by mass spectrometry in combination with one and two dimensional NMR, including HMBC. Both compounds inhibited prostaglandin biosynthesis in vitro, alphitol with an IC50 value of 0.66 mM, which is of the same magnitude as acetyl salicylic acid.

  • 17.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.

    List of papers
    1. Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Open this publication in new window or tab >>Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Show others...
    2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 7, p. 434-444Article in journal (Refereed) Published
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

    Keywords
    Adult neural stem cells, Angiotensin IV, Bioactive conformation, Insulin-regulated aminopeptidase, IRAP, Peptide synthesis, Peptidemimetic, Structure-activity relationship, Turn mimetic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16622 (URN)10.1002/psc.859 (DOI)000248164400002 ()17559064 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-03-20Bibliographically approved
    2. Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Open this publication in new window or tab >>Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Show others...
    2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 14, p. 6924-6935Article in journal (Refereed) Published
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

    Keywords
    Angiotensin IV, Insulin-regulated aminopeptidase (IRAP), Cystinyl aminopeptidase (CAP), Aminopeptidase N (AP-N), Structure–activity relationship, Peptide synthesis, Peptide mimetic, 4-Hydroxydiphenylmethane, Tyrosine mimetic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102954 (URN)10.1016/j.bmc.2008.05.046 (DOI)000257829600031 ()18556208 (PubMedID)
    Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2018-03-20Bibliographically approved
    3. Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Open this publication in new window or tab >>Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Show others...
    2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 22, p. 8059-8071Article in journal (Refereed) Published
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

    Keywords
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, disulfide, NAMFIS
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-122213 (URN)10.1021/jm100793t (DOI)000284287200016 ()21047126 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2018-03-20Bibliographically approved
    4. Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
    Open this publication in new window or tab >>Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
    Show others...
    2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed) Published
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

    Keywords
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, macrocyclic, ring-closing metathesis
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-122208 (URN)10.1021/jm200036n (DOI)000291082500008 ()21476495 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2018-05-29Bibliographically approved
  • 18.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

  • 19.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Vauquelin, Georges
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr22008In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 14, p. 6924-6935Article in journal (Refereed)
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

  • 20.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 22, p. 8059-8071Article in journal (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

  • 21.
    Andersson, Hans O.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Fridborg, Kerstin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Löwgren, Seved
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mühlman, Anna
    Björsne, Magnus
    Garg, Neeraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kvarnström, Ingemar
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Classon, Björn
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Vrang, Lotta
    Öberg, Bo
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 8, p. 1746-1758Article in journal (Refereed)
  • 22.
    Appukkuttan, Prasad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Axelsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Van der Eycken, Erik
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up2008In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 39, p. 5625-5628Article in journal (Refereed)
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

  • 23.
    Arefalk, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Masked 3-Aminoindan-1-ones by a Palladium-Catalyzed Three-Component Annulation Reaction2005In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, no 3, p. 938-942Article in journal (Refereed)
  • 24.
    Arefalk, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wannberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.