Q4 · MEDICINE
Article
Author: Zhou, Yun-Ping ; Samuel, Koppara ; Morissette, Pierre ; Shah, Shrenik K ; Chicchi, Gary G ; Hagmann, William K ; Liu, Jian ; Wu, Margaret ; He, Shuwen ; Feng, Zhe ; Nelson, Donald ; Jian, Tianying ; Kerr, Janet ; Fernandez, Guillermo ; Guo, Liangqin ; Zhang, Bei B ; Howard, Andrew D ; Li, Cai ; Ye, Zhixiong ; Nargund, Ravi P ; Trujillo, Maria E ; Fitzgerald, Patrick ; Sherer, Edward ; Trusca, Dorina ; Mitelman, Stan ; Dobbelaar, Peter H ; Bunting, Patricia ; Pasternak, Alexander ; Du, Wu ; Reibarkh, Mikhail ; Truong, Quang ; Hong, Qingmei ; Eiermann, George J ; Tsao, Kwei-Lan ; Reddy, Vijay B ; Qi, Hongbo ; Shao, Qing ; Lin, Melissa ; Volksdorf, Sylvia ; Dellureficio, James D ; Tong, Sharon X ; Bakshi, Raman K
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.