1428533-35-0Relevant articles and documents
Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket
Gising, Johan,Belfrage, Anna Karin,Alogheli, Hiba,Ehrenberg, Angelica,?kerblom, Eva,Svensson, Richard,Artursson, Per,Karlén, Anders,Danielson, U. Helena,Larhed, Mats,Sandstr?m, Anja
supporting information, p. 1790 - 1801 (2014/04/03)
Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
