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Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
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: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, no 3, 249-254 p.Article 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.

Place, publisher, year, edition, pages
2014. Vol. 5, no 3, 249-254 p.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-221229DOI: 10.1021/ml400217rISI: 000333006200005OAI: oai:DiVA.org:uu-221229DiVA: diva2:708059
Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2017-12-05Bibliographically approved

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Bergman, SaraAlogheli, HibaÅkerblom, EvaLindeberg, GunnarSvensson, RichardArtursson, PerDanielsson, Helena U.Karlén, AndersSandström, Anja

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Bergman, SaraAlogheli, HibaÅkerblom, EvaLindeberg, GunnarSvensson, RichardArtursson, PerDanielsson, Helena U.Karlén, AndersSandström, Anja
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Organic Pharmaceutical ChemistryDepartment of Chemistry - BMCDepartment of PharmacyBiochemistry
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