With the introduction of inhibitors of the HCV serine protease NS3/4a such as boceprevir and telaprevir, given in combination with interferon and ribavirin, the sustained virological response rate has improved to up to 75% for na�ve HCV gentotype 1 patients. Additional NS3/4a protease inhibitors with broad genotype activity are currently being investigated as interferon sparing all-oral regimens. We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which is currently undergoing clinical trials. 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 sub-site, 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 gt-1b A156 mutants.

Novel quinoline-based P2-P4 macrocyclic derivatives as pan-genotypic HCV NS3/4a protease inhibitors

247th National Meeting (2014)

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