SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists. Issue 6 (15th March 2016)

• Record Type: Journal Article
• Authors: He, Shuwen; Dobbelaar, Peter H.; Guo, Liangqin; Ye, Zhixiong; Liu, Jian; Jian, Tianying; Truong, Quang; Shah, Shrenik K.; Du, Wu; Qi, Hongbo; Bakshi, Raman K.; Hong, Qingmei; Dellureficio, James D.; Sherer, Edward; Pasternak, Alexander; Feng, Zhe; Reibarkh, Mikhail; Lin, Melissa; Samuel, Koppara; Reddy, Vijay B.; Mitelman, Stan; Tong, Sharon X.; Chicchi, Gary G.; Tsao, Kwei-Lan; Trusca, Dorina; Wu, Margaret; Shao, Qing; Trujillo, Maria E.; Fernandez, Guillermo; Nelson, Donald; Bunting, Patricia; Kerr, Janet; Fitzgerald, Patrick; Morissette, Pierre; Volksdorf, Sylvia; Eiermann, George J.; Li, Cai; Zhang, Bei B.; Howard, Andrew D.; Zhou, Yun-Ping; Nargund, Ravi P.; Hagmann, William K.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 6(2016)
• Page Start: 1529
• Page End: 1535
• Publication Date: 2016-03-15
• Subjects: Somatostatin receptor subtype 3 -- Antagonist -- Tetrahydro-β-carboline -- hERG -- SAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.02.022
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical 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 hERG off-target liability. 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.