Document Report Card

ID: ALA3120153

Journal: ACS Med Chem Lett

Title: Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.

Authors: Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.

Abstract: We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.

CiteXplore: 24900818

DOI: 10.1021/ml400466p