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.
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.
Venkatraman
Srikanth
S
Schering Plough Research Institute, K-15, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Srikanth.Venkatraman@spcorp.com
Bogen
Stéphane L
SL
Arasappan
Ashok
A
Bennett
Frank
F
Chen
Kevin
K
Jao
Edwin
E
Liu
Yi-Tsung
YT
Lovey
Raymond
R
Hendrata
Siska
S
Huang
Yuhua
Y
Pan
Weidong
W
Parekh
Tejal
T
Pinto
Patrick
P
Popov
Veljko
V
Pike
Russel
R
Ruan
Sumei
S
Santhanam
Bama
B
Vibulbhan
Bancha
B
Wu
Wanli
W
Yang
Weiying
W
Kong
Jianshe
J
Liang
Xiang
X
Wong
Jesse
J
Liu
Rong
R
Butkiewicz
Nancy
N
Chase
Robert
R
Hart
Andrea
A
Agrawal
Sony
S
Ingravallo
Paul
P
Pichardo
John
J
Kong
Rong
R
Baroudy
Bahige
B
Malcolm
Bruce
B
Guo
Zhuyan
Z
Prongay
Andrew
A
Madison
Vincent
V
Broske
Lisa
L
Cui
Xiaoming
X
Cheng
Kuo-Chi
KC
Hsieh
Yunsheng
Y
Brisson
Jean-Marc
JM
Prelusky
Danial
D
Korfmacher
Walter
W
White
Ronald
R
Bogdanowich-Knipp
Susan
S
Pavlovsky
Anastasia
A
Bradley
Prudence
P
Saksena
Anil K
AK
Ganguly
Ashit
A
Piwinski
John
J
Girijavallabhan
Viyyoor
V
Njoroge
F George
FG
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
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