title: Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. gopalsa@wyeth.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Kitae
authors.initials: K
authors.lastname: Lim
authors.forename: Gregory
authors.initials: G
authors.lastname: Ciszewski
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Curran
authors.forename: Steven F
authors.initials: SF
authors.lastname: Sukits
authors.forename: Kristine
authors.initials: K
authors.lastname: Svenson
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Atul
authors.initials: A
authors.lastname: Agarwal
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.forename: Mark
authors.initials: M
authors.lastname: Orlowski
authors.forename: Boris
authors.initials: B
authors.lastname: Feld
authors.forename: John
authors.initials: J
authors.lastname: O'Connell
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011392:Proline; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase