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Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2014 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, no 23, 6595-6615 p.Article 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.

Place, publisher, year, edition, pages
2014. Vol. 22, no 23, 6595-6615 p.
Keyword [en]
HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-239738DOI: 10.1016/j.bmc.2014.10.010ISI: 000345287300007OAI: oai:DiVA.org:uu-239738DiVA: diva2:775296
Available from: 2014-12-31 Created: 2014-12-30 Last updated: 2017-12-05Bibliographically approved

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Alogheli, HibaÅkerblom, EvaSvensson, RichardArtursson, PerDanielson, HelenaKarlén, AndersSandström, Anja

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Alogheli, HibaÅkerblom, EvaSvensson, RichardArtursson, PerDanielson, HelenaKarlén, AndersSandström, Anja
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Organic Pharmaceutical ChemistryDepartment of Chemistry - BMCDepartment of PharmacyBiochemistry
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