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Discovery of Proline Sulfonamides as Potent and Selective Hepatitis C Virus NS5b Polymerase Inhibitors. Evidence for a New NS5b Polymerase Binding Site

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journal contribution
posted on 01.06.2006 by Ariamala Gopalsamy, Rajiv Chopra, Kitae Lim, Gregory Ciszewski, Mengxiao Shi, Kevin J. Curran, Steven F. Sukits, Kristine Svenson, Joel Bard, John W. Ellingboe, Atul Agarwal, Girija Krishnamurthy, Anita Y. M. Howe, Mark Orlowski, Boris Feld, John O'Connell, Tarek S. Mansour
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.