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SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists
Shuwen He1, Peter H Dobbelaar1, Liangqin Guo1
1Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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.
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