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SAR development of palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead I 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. Further SAR development resulted in novel NS5B polymerase inhibitors exemplified by 7r with improved enzyme and replicon activity.
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC50=0.9μM, replicon EC50>100μM) 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 IC50=0.032μM, replicon EC50=1.4μM) and 7r (NS5B IC50=0.017μM, replicon EC50=0.3μM) with improved enzyme and replicon activity.