Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease.
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating 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 a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.
Venkatraman
Srikanth
S
Schering Plough Research Institute, K-15, MS-3545, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Srikanth.Venkatraman@spcorp.com
Velazquez
Francisco
F
Wu
Wanli
W
Blackman
Melissa
M
Chen
Kevin X
KX
Bogen
Stephane
S
Nair
Latha
L
Tong
Xiao
X
Chase
Robert
R
Hart
Andrea
A
Agrawal
Sony
S
Pichardo
John
J
Prongay
Andrew
A
Cheng
Kuo-Chi
KC
Girijavallabhan
Viyyoor
V
Piwinski
John
J
Shih
Neng-Yang
NY
Njoroge
F George
FG
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006860:Hydrogen Bonding; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases