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