Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site.
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.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. gopalsa@wyeth.com
Chopra
Rajiv
R
Lim
Kitae
K
Ciszewski
Gregory
G
Shi
Mengxiao
M
Curran
Kevin J
KJ
Sukits
Steven F
SF
Svenson
Kristine
K
Bard
Joel
J
Ellingboe
John W
JW
Agarwal
Atul
A
Krishnamurthy
Girija
G
Howe
Anita Y M
AY
Orlowski
Mark
M
Feld
Boris
B
O'Connell
John
J
Mansour
Tarek S
TS
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
D000998:Antiviral Agents; D011392:Proline; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase