Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

Shrenik K Shah; Shuwen He; Liangqin Guo; Quang Truong; Hongbo Qi; Wu Du; Zhong Lai; Jian Liu; Tianying Jian; Qingmei Hong; Peter Dobbelaar; Zhixiong Ye; Edward Sherer; Zhe Feng; Yang Yu; Frederick Wong; Koppara Samuel; Maria Madiera; Bindhu V Karanam; Vijay B Reddy; Stan Mitelman; Sharon X Tong; Gary G Chicchi; Kwei-Lan Tsao; Dorina Trusca; Yue Feng; Margaret Wu; Qing Shao; Maria E Trujillo; George J Eiermann; Cai Li; Michele Pachanski; Guillermo Fernandez; Donald Nelson; Patricia Bunting; Pierre Morissette; Sylvia Volksdorf; Janet Kerr; Bei B Zhang; Andrew D Howard; Yun-Ping Zhou; Alexander Pasternak; Ravi P Nargund; William K Hagmann

doi:10.1021/ml500514w

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

ACS Med Chem Lett. 2015 Mar 18;6(5):513-7. doi: 10.1021/ml500514w. eCollection 2015 May 14.

Authors

Shrenik K Shah¹, Shuwen He¹, Liangqin Guo¹, Quang Truong¹, Hongbo Qi¹, Wu Du¹, Zhong Lai¹, Jian Liu¹, Tianying Jian¹, Qingmei Hong¹, Peter Dobbelaar¹, Zhixiong Ye¹, Edward Sherer¹, Zhe Feng¹, Yang Yu¹, Frederick Wong¹, Koppara Samuel¹, Maria Madiera¹, Bindhu V Karanam¹, Vijay B Reddy¹, Stan Mitelman¹, Sharon X Tong¹, Gary G Chicchi¹, Kwei-Lan Tsao¹, Dorina Trusca¹, Yue Feng¹, Margaret Wu¹, Qing Shao¹, Maria E Trujillo¹, George J Eiermann¹, Cai Li¹, Michele Pachanski¹, Guillermo Fernandez², Donald Nelson², Patricia Bunting², Pierre Morissette², Sylvia Volksdorf², Janet Kerr², Bei B Zhang¹, Andrew D Howard¹, Yun-Ping Zhou¹, Alexander Pasternak¹, Ravi P Nargund¹, William K Hagmann¹

Affiliations

¹ 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.
² Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.

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).

Keywords: antagonist; sstr3; tetrahydro-β-carboline; type 2 diabetes.