title: I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
abstract: SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. gopinadhan.anilkumar@merck.com
authors.forename: Gopinadhan N
authors.initials: GN
authors.lastname: Anilkumar
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesburg
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Rosenblum
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Pu
authors.forename: Henry
authors.initials: H
authors.lastname: Vaccaro
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Jose
authors.initials: J
authors.lastname: Duca
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Mousumi
authors.initials: M
authors.lastname: Sannigrahi
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Nancy
authors.initials: N
authors.lastname: Butkiewicz
authors.forename: Boris
authors.initials: B
authors.lastname: Feld
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrari
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: He
authors.forename: Chuan-Kui
authors.initials: CK
authors.lastname: Jiang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.forename: Patricia
authors.initials: P
authors.lastname: McMonagle
authors.forename: H-C
authors.initials: HC
authors.lastname: Huang
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: George
authors.initials: G
authors.lastname: Njoroge
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
mesh_terms: D002264:Carboxylic Acids; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007211:Indoles; D017361:Viral Nonstructural Proteins; C058980:indole-2-carboxylic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase