title: A novel class of highly potent irreversible hepatitis C virus NS5B polymerase inhibitors.
abstract: Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. kxcn@yahoo.com
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesburg
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Weiying
authors.initials: W
authors.lastname: Yang
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Gopinadhan N
authors.initials: GN
authors.lastname: Anilkumar
authors.forename: Jose
authors.initials: J
authors.lastname: Duca
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Haiyan
authors.initials: H
authors.lastname: Pu
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Boris
authors.initials: B
authors.lastname: Feld
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Rosenblum
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D009574:Nitro Compounds; D011728:Pyridones; D013450:Sulfones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase