title: Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity.
abstract: HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: wensheng.yu@merck.com.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: De-Yi
authors.initials: DY
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Rosenblum
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Njoroge
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Anilkumar G
authors.initials: AG
authors.lastname: Nair
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhong
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ji
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Xia
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Kong
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ingravallo
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.affiliation: Department of PPDM, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.affiliation: Department of Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: James
authors.initials: J
authors.lastname: Fells
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Direct-acting antiviral agents (DAA); Elbasvir; HCV NS5A inhibitor; Hepatitis C; Pan-genotype activity; Tricyclic