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J Med Chem. 2014 Mar 13;57(5):1770-6. doi: 10.1021/jm400121t. Epub 2013 Mar 28.

Discovery of hepatitis C virus NS3-4A protease inhibitors with improved barrier to resistance and favorable liver distribution.

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Department of Medicinal Chemistry and ‡Department of Biological Sciences, Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.


Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.

[Indexed for MEDLINE]

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