P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl α-ketoamide based HCV protease inhibitors

With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1′, P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50 mg/kg, 3a achieved 2.5× higher liver and plasma exposure in comparison to that detected with 1a. We describe herein the discovery of LY526181, a P2 bicycloproline tetrapeptidyl α-ketoamide HCV protease inhibitor with desirable antiviral activity, ADME and toxicological profile.