title: Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742.
abstract: As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: wensheng.yu@merck.com.
authors: Wensheng
authors: W
authors: Yu
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Guowei
authors: G
authors: Zhou
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors: Craig A
authors: CA
authors: Coburn
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Qingbei
authors: Q
authors: Zeng
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Ling
authors: L
authors: Tong
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Michael P
authors: MP
authors: Dwyer
authors: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors: Bin
authors: B
authors: Hu
authors: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors: Bin
authors: B
authors: Zhong
authors: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors: Jinglai
authors: J
authors: Hao
authors: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors: Tao
authors: T
authors: Ji
authors: WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
authors: Shuai
authors: S
authors: Zan
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Lei
authors: L
authors: Chen
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Robert
authors: R
authors: Mazzola
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Jae-Hun
authors: JH
authors: Kim
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Deyou
authors: D
authors: Sha
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Oleg
authors: O
authors: Selyutin
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Stuart B
authors: SB
authors: Rosenblum
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Brian
authors: B
authors: Lavey
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Anilkumar G
authors: AG
authors: Nair
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Seong
authors: S
authors: Heon Kim
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Kerry M
authors: KM
authors: Keertikar
authors: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Laura
authors: L
authors: Rokosz
authors: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Sony
authors: S
authors: Agrawal
authors: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Rong
authors: R
authors: Liu
authors: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Ellen
authors: E
authors: Xia
authors: Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Ying
authors: Y
authors: Zhai
authors: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Stephanie
authors: S
authors: Curry
authors: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Patricia
authors: P
authors: McMonagle
authors: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Paul
authors: P
authors: Ingravallo
authors: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Ernest
authors: E
authors: Asante-Appiah
authors: Department of PPDM, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Shiying
authors: S
authors: Chen
authors: Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
authors: Joseph A
authors: JA
authors: Kozlowski
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; 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; D007211:Indoles; D017361:Viral Nonstructural Proteins; C000589335:elbasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Elbasvir; HCV DAA; HCV NS5A inhibitor; HCV infection; MK-8742; Resistance associated variants