title: Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.
abstract: 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 K i-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.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Lampa
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Bergman
authors.affiliation: Department of Chemistry-BMC, Uppsala University , BMC, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Sofia S
authors.initials: SS
authors.lastname: Gustafsson
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Hiba
authors.initials: H
authors.lastname: Alogheli
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Eva B
authors.initials: EB
authors.lastname: Akerblom
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Gunnar G
authors.initials: GG
authors.lastname: Lindeberg
authors.affiliation: Department of Pharmacy, Uppsala University , Box 580, SE-751 23 Uppsala, Sweden ; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University , a Node of the Chemical Biology Consortium Sweden (CBCS), Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Svensson
authors.affiliation: Department of Pharmacy, Uppsala University , Box 580, SE-751 23 Uppsala, Sweden ; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University , a Node of the Chemical Biology Consortium Sweden (CBCS), Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Department of Chemistry-BMC, Uppsala University , BMC, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
keywords: HCV; NS3; peptidomimetics; phenylglycine; protease inhibitors