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- I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
Bioorganic & medicinal chemistry letters (2011-08-16)
Gopinadhan N Anilkumar, Charles A Lesburg, Oleg Selyutin, Stuart B Rosenblum, Qingbei Zeng, Yueheng Jiang, Tin-Yau Chan, Haiyan Pu, Henry Vaccaro, Li Wang, Frank Bennett, Kevin X Chen, Jose Duca, Stephen Gavalas, Yuhua Huang, Patrick Pinto, Mousumi Sannigrahi, Francisco Velazquez, Srikanth Venkatraman, Bancha Vibulbhan, Sony Agrawal, Nancy Butkiewicz, Boris Feld, Eric Ferrari, Zhiqing He, Chuan-Kui Jiang, Robert E Palermo, Patricia McMonagle, H-C Huang, Neng-Yang Shih, George Njoroge, Joseph A Kozlowski
PMID21840715
摘要
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) 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 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.
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