Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding

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 polymera...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 49; no. 11; pp. 3052 - 3055
Main Authors Gopalsamy, Ariamala, Chopra, Rajiv, Lim, Kitae, Ciszewski, Gregory, Shi, Mengxiao, Curran, Kevin J., Sukits, Steven F., Svenson, Kristine, Bard, Joel, Ellingboe, John W., Agarwal, Atul, Krishnamurthy, Girija, Howe, Anita Y. M., Orlowski, Mark, Feld, Boris, O'Connell, John, Mansour, Tarek S.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 01.06.2006
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
DEPENDENT RNA-POLYMERASE
Online AccessGet full text

Cover

More Information
Summary: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.
ISSN:0022-2623
DOI:10.1021/jm060168g