SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

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• 作者：Shuwen He ; ^{shuwen_he@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Peter H. Dobbelaar ; Liangqin Guo ; Zhixiong Ye ; Jian Liu ; Tianying Jian ; Quang Truong ; Shrenik K. Shah ; Wu Du ; Hongbo Qi ; Raman K. Bakshi ; Qingmei Hong ; James D. Dellureficio ; Edward Sherer ; Alexander Pasternak ; Zhe Feng ; Mikhail Reibarkh ; Melissa Lin ; Koppara Samuel ; Vijay B. Reddy ; Stan Mitelman ; Sharon X. Tong ; Gary G. Chicchi ; Kwei-Lan Tsao ; Dorina Trusca ; Margaret Wu ; Qing Shao ; Maria E. Trujillo ; Guillermo Fernandez ; Donald Nelson ; Patricia Bunting ; Janet Kerr ; Patrick Fitzgerald ; Pierre Morissette ; Sylvia Volksdorf ; George J. Eiermann ; Cai Li ; Bei B. Zhang ; Andrew D. Howard ; Yun-Ping Zhou ; Ravi P. Nargund ; William K. Hagmann
• 关键词：Somatostatin receptor subtype 3 ; Antagonist ; Tetrahydro-β-carboline ; hERG ; SAR
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：26
• 期：6
• 页码：1529-1535
• 全文大小：3036 K

文摘

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.