title: Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease.
abstract: 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.
authors.affiliation: Schering Plough Research Institute, K-15, MS-3545, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Srikanth.Venkatraman@spcorp.com
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Wanli
authors.initials: W
authors.lastname: Wu
authors.forename: Melissa
authors.initials: M
authors.lastname: Blackman
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Stephane
authors.initials: S
authors.lastname: Bogen
authors.forename: Latha
authors.initials: L
authors.lastname: Nair
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
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: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: John
authors.initials: J
authors.lastname: Piwinski
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: 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
chemical_list: 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