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

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journal contribution
posted on 2015-12-22, 19:17 authored by 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
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).