title: Optimization of potency and pharmacokinetics of tricyclic indole derived inhibitors of HCV NS5B polymerase. Identification of ester prodrugs with improved oral pharmacokinetics.
abstract: HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current efforts are directed towards identification of novel direct acting antiviral targeting different mechanism of actions which could become part of all oral therapies. We recently disclosed the identification of a novel tricyclic indole derived inhibitors of HCV NS5B polymerase that bound to the enzyme close to the active site. In this manuscript we describe further optimization of potency and pharmacokinetics (PK) of these inhibitors to identify compounds in low nM potency against gt-1b. These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug.
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: Srikanth.Venkatraman@merck.com.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Wanli
authors.initials: W
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Anilkumar G
authors.initials: AG
authors.lastname: Nair
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Lesburg
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Duca
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Larry
authors.initials: L
authors.lastname: Heimark
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Chuan-kui
authors.initials: CK
authors.lastname: Jiang
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Stuart
authors.initials: S
authors.lastname: Rosenblum
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.affiliation: Merck Research Laboratories, K15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D004952:Esters / Q000737:chemistry / Q000493:pharmacokinetics*; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004952:Esters; D007211:Indoles; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C030374:indole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Dimethylamino ethyl; HCV NS5B; Polymerase; Prodrug; Tricyclic indole