title: Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.
abstract: The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shrenik K
authors.initials: SK
authors.lastname: Shah
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Liangqin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qi
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Wu
authors.initials: W
authors.lastname: Du
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Dobbelaar
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Sherer
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Wong
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Koppara
authors.initials: K
authors.lastname: Samuel
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madiera
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Bindhu V
authors.initials: BV
authors.lastname: Karanam
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Vijay B
authors.initials: VB
authors.lastname: Reddy
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Mitelman
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Tong
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dorina
authors.initials: D
authors.lastname: Trusca
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wu
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Trujillo
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Pachanski
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernandez
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Donald
authors.initials: D
authors.lastname: Nelson
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bunting
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morissette
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Volksdorf
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: Kerr
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
keywords: antagonist; sstr3; tetrahydro-β-carboline; type 2 diabetes