title: Structure-activity relationship (SAR) development and discovery of potent indole-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase.
abstract: Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States. kxcn@yahoo.com
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Weiying
authors.initials: W
authors.lastname: Yang
authors.forename: Mousumi
authors.initials: M
authors.lastname: Sannigrahi
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Gopinadhan N
authors.initials: GN
authors.lastname: Anilkumar
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.forename: Frank
authors.initials: F
authors.lastname: Bennet
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesburg
authors.forename: Jose
authors.initials: J
authors.lastname: Duca
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Wanli
authors.initials: W
authors.lastname: Wu
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
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: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D051381:Rats; D012093:Replicon; D013329:Structure-Activity Relationship; D013449:Sulfonamides / 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; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C571184:N-(cyclopropylsulfonyl)-1-((2,5-difluorophenyl)methyl)-3-(1,2-dihydro-2-oxo-3-pyridinyl)-6-fluoro-5-(methyl)-1H-indole-2-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase