title: Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists.
abstract: Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Shuwen
authors: S
authors: He
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Zhong
authors: Z
authors: Lai
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Zhixiong
authors: Z
authors: Ye
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Peter H
authors: PH
authors: Dobbelaar
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Shrenik K
authors: SK
authors: Shah
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Quang
authors: Q
authors: Truong
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Wu
authors: W
authors: Du
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Liangqin
authors: L
authors: Guo
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Jian
authors: J
authors: Liu
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Tianying
authors: T
authors: Jian
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Hongbo
authors: H
authors: Qi
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Raman K
authors: RK
authors: Bakshi
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Qingmei
authors: Q
authors: Hong
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: James
authors: J
authors: Dellureficio
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Mikhail
authors: M
authors: Reibarkh
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Koppara
authors: K
authors: Samuel
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Vijay B
authors: VB
authors: Reddy
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Stan
authors: S
authors: Mitelman
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Sharon X
authors: SX
authors: Tong
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Gary G
authors: GG
authors: Chicchi
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Kwei-Lan
authors: KL
authors: Tsao
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Dorina
authors: D
authors: Trusca
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Margaret
authors: M
authors: Wu
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Qing
authors: Q
authors: Shao
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Maria E
authors: ME
authors: Trujillo
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Guillermo
authors: G
authors: Fernandez
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Donald
authors: D
authors: Nelson
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Patricia
authors: P
authors: Bunting
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Janet
authors: J
authors: Kerr
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Patrick
authors: P
authors: Fitzgerald
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Pierre
authors: P
authors: Morissette
authors: Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Sylvia
authors: S
authors: Volksdorf
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: George J
authors: GJ
authors: Eiermann
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Cai
authors: C
authors: Li
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Bei
authors: B
authors: Zhang
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Andrew D
authors: AD
authors: Howard
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Yun-Ping
authors: YP
authors: Zhou
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Ravi P
authors: RP
authors: Nargund
authors: Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: William K
authors: WK
authors: Hagmann
keywords: QTc prolongation; Type-2 diabetes; antagonist; carboxylic acid; cardiovascular dog models; hERG channel; sstr3; β-tetrahydrocarboline