I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50) = 0.9 mu M, replicon EC(50) > 100 mu M) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50) = 0.032 mu M, replicon EC(50) = 1.4 mu M) and 7r (NS5B IC(50) = 0.017 mu M, replicon EC(50) = 0.3 mu M) with improved enzyme and replicon activity. (C) 2011 Elsevier Ltd. All rights reserved.