| Literature DB >> 26898814 |
Shuwen He1, Peter H Dobbelaar2, Liangqin Guo2, Zhixiong Ye2, Jian Liu2, Tianying Jian2, Quang Truong2, Shrenik K Shah2, Wu Du2, Hongbo Qi2, Raman K Bakshi2, Qingmei Hong2, James D Dellureficio2, Edward Sherer2, Alexander Pasternak2, Zhe Feng2, Mikhail Reibarkh2, Melissa Lin2, Koppara Samuel2, Vijay B Reddy2, Stan Mitelman2, Sharon X Tong2, Gary G Chicchi2, Kwei-Lan Tsao2, Dorina Trusca2, Margaret Wu2, Qing Shao2, Maria E Trujillo2, Guillermo Fernandez2, Donald Nelson2, Patricia Bunting2, Janet Kerr2, Patrick Fitzgerald2, Pierre Morissette2, Sylvia Volksdorf2, George J Eiermann2, Cai Li2, Bei B Zhang2, Andrew D Howard2, Yun-Ping Zhou2, Ravi P Nargund2, William K Hagmann2.
Abstract
MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.Entities:
Keywords: Antagonist; SAR; Somatostatin receptor subtype 3; Tetrahydro-β-carboline; hERG
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Year: 2016 PMID： 26898814 DOI： 10.1016/j.bmcl.2016.02.022
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823