2. Academic Validation
  3. Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

  • ACS Med Chem Lett. 2014 Apr 21;5(7):748-53. doi: 10.1021/ml500028c.
Shuwen He 1,  Zhong Lai 1,  Zhixiong Ye 1,  Peter H Dobbelaar 1,  Shrenik K Shah 1,  Quang Truong 1,  Wu Du 1,  Liangqin Guo 1,  Jian Liu 1,  Tianying Jian 1,  Hongbo Qi 1,  Raman K Bakshi 1,  Qingmei Hong 1,  James Dellureficio 1,  Mikhail Reibarkh 1,  Koppara Samuel 1,  Vijay B Reddy 1,  Stan Mitelman 1,  Sharon X Tong 1,  Gary G Chicchi 1,  Kwei-Lan Tsao 1,  Dorina Trusca 1,  Margaret Wu 1,  Qing Shao 1,  Maria E Trujillo 1,  Guillermo Fernandez 2,  Donald Nelson 2,  Patricia Bunting 2,  Janet Kerr 2,  Patrick Fitzgerald 2,  Pierre Morissette 2,  Sylvia Volksdorf 2,  George J Eiermann 1,  Cai Li 1,  Bei Zhang 1,  Andrew D Howard 1,  Yun-Ping Zhou 1,  Ravi P Nargund 1,  William K Hagmann 1
Affiliations

Affiliations

  • 1 Merck Research Laboratories , Departments of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics, and Diabetes Research, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 2 Department of Safety Assessment, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
PMID: 25050159 DOI: 10.1021/ml500028c
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.

Keywords

QTc prolongation; Type-2 diabetes; antagonist; carboxylic acid; cardiovascular dog models; hERG channel; sstr3; β-tetrahydrocarboline.

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