402958-99-0Relevant articles and documents
P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors
Yip, Yvonne,Victor, Frantz,Lamar, Jason,Johnson, Robert,Wang, Q. May,Glass, John I.,Yumibe, Nathan,Wakulchik, Mark,Munroe, John,Chen, Shu-Hui
, p. 5007 - 5011 (2007/10/03)
We describe herein the design, synthesis, and antiviral activity of a series of P4 modified tetrapeptidyl α-ketoamides as HCV protease inhibitors. The most promising analog identified through this SAR, 5a, 5c, and 5e demonstrated excellent enzyme inhibitory potency, enzyme selectivity, cellular activity, and acceptable therapeutic indexes. With the aim of improving HCV protease inhibitors reported in our previous manuscripts, we synthesized and evaluated a series of 1a-based tetrapeptidyl α-ketoamides with additional P4 modification. The promising analog discovered through this SAR, 5a, was further derivatized at P1′ or P1 position. As a result of these efforts, we found that replacement of the P4 valine as seen in 1a with cyclohexylglycine (Chg) resulted in the discovery of 5a, 5c, and 5e endowed with improved cellular activity in comparison to 1a.
