title: Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.
abstract: Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
authors.affiliation: Schering Plough Research Institute, K-15, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Srikanth.Venkatraman@spcorp.com
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Stéphane L
authors.initials: SL
authors.lastname: Bogen
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Edwin
authors.initials: E
authors.lastname: Jao
authors.forename: Yi-Tsung
authors.initials: YT
authors.lastname: Liu
authors.forename: Raymond
authors.initials: R
authors.lastname: Lovey
authors.forename: Siska
authors.initials: S
authors.lastname: Hendrata
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.forename: Tejal
authors.initials: T
authors.lastname: Parekh
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Veljko
authors.initials: V
authors.lastname: Popov
authors.forename: Russel
authors.initials: R
authors.lastname: Pike
authors.forename: Sumei
authors.initials: S
authors.lastname: Ruan
authors.forename: Bama
authors.initials: B
authors.lastname: Santhanam
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Wanli
authors.initials: W
authors.lastname: Wu
authors.forename: Weiying
authors.initials: W
authors.lastname: Yang
authors.forename: Jianshe
authors.initials: J
authors.lastname: Kong
authors.forename: Xiang
authors.initials: X
authors.lastname: Liang
authors.forename: Jesse
authors.initials: J
authors.lastname: Wong
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Nancy
authors.initials: N
authors.lastname: Butkiewicz
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.forename: Andrea
authors.initials: A
authors.lastname: Hart
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Paul
authors.initials: P
authors.lastname: Ingravallo
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Rong
authors.initials: R
authors.lastname: Kong
authors.forename: Bahige
authors.initials: B
authors.lastname: Baroudy
authors.forename: Bruce
authors.initials: B
authors.lastname: Malcolm
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: Lisa
authors.initials: L
authors.lastname: Broske
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cui
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Brisson
authors.forename: Danial
authors.initials: D
authors.lastname: Prelusky
authors.forename: Walter
authors.initials: W
authors.lastname: Korfmacher
authors.forename: Ronald
authors.initials: R
authors.lastname: White
authors.forename: Susan
authors.initials: S
authors.lastname: Bogdanowich-Knipp
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pavlovsky
authors.forename: Prudence
authors.initials: P
authors.lastname: Bradley
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saksena
authors.forename: Ashit
authors.initials: A
authors.lastname: Ganguly
authors.forename: John
authors.initials: J
authors.lastname: Piwinski
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000201:enzymology*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011392:Proline; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide