title: Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742.
abstract: Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
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: 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: 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: Guowei
authors.initials: G
authors.lastname: Zhou
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: Ling
authors.initials: L
authors.lastname: Tong
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
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: Jinglai
authors.initials: J
authors.lastname: Hao
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: Shuai
authors.initials: S
authors.lastname: Zan
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
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: 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: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Masse
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 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 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: Stephanie
authors.initials: S
authors.lastname: Curry
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: McMonagle
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: Mingxiang
authors.initials: M
authors.lastname: Lin
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: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D007093:Imidazoles; D017361:Viral Nonstructural Proteins; C000589335:elbasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Direct-acting antiviral agent (DAA); Elbasvir; HCV NS5A inhibitor; HCV infection; HCV resistance associated variants; MK-8742; Pan-genotype activity