Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.

Autor: Lampa AK; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Bergman SM; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Gustafsson SS; Department of Chemistry-BMC, Uppsala University , BMC, Box 576, SE-751 23 Uppsala, Sweden., Alogheli H; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Akerblom EB; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Lindeberg GG; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Svensson RM; 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., Artursson P; 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., Danielson UH; Department of Chemistry-BMC, Uppsala University , BMC, Box 576, SE-751 23 Uppsala, Sweden., Karlén A; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden., Sandström A; Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University , BMC, Box 574, SE-751 23 Uppsala, Sweden.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2013 Aug 02; Vol. 5 (3), pp. 249-54. Date of Electronic Publication: 2013 Aug 02 (Print Publication: 2014).
DOI: 10.1021/ml400217r
Abstrakt: 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.
Databáze: MEDLINE