MEDI 87

Recent efforts in the field of Hepatitis C research have focused on attempts to discover new small molecule drug combinations to compliment or replace Pegylated Interferon/Ribavirin, the current standard of care. This treatment is effective for less than 50% of patients with Genotype 1 virus, and many debilitating side effects often result in the discontinuation of therapy. During the course of our research in peptidomimetic HCV Protease inhibitors, we became interested in the optimization of inhibitor-enzyme interactions in the S1` pocket. This poster examines the incorporation of macrocyclic P1-P1' acylsulfamides (1) as well as acyclic acyl-sulfamides into known HCV protease P2-P4 cores to explore the S1` pocket. Molecular modeling was utilized throughout the design process. The solution to synthetic challenges and IC₅₀ values for these inhibitors, with some having single digit to sub-mmol activity against genotype1 HCV protease, are reported.