Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.

Gising J, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A

J. Med. Chem. 57 (5) 1790-1801 [2014-03-13; online 2013-03-23]

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 R(6) 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 R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

PubMed 23517538

DOI 10.1021/jm301887f

Crossref 10.1021/jm301887f

Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)
ADME of Therapeutics (UDOPP)