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

Bioorganic & Medicinal Chemistry Letters
Shuwen HeWilliam K Hagmann

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.

References

Aug 25, 2001·Journal of Medicinal Chemistry·L PoitoutC Thurieau
Apr 12, 2012·ACS Medicinal Chemistry Letters·Alexander PasternakYun-Ping Zhou
Jun 14, 2012·ACS Medicinal Chemistry Letters·Shuwen HeWilliam K Hagmann
Jul 23, 2014·ACS Medicinal Chemistry Letters·Shuwen HeWilliam K Hagmann
May 26, 2015·ACS Medicinal Chemistry Letters·Shrenik K ShahWilliam K Hagmann

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