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

• Published in: Bioorganic & medicinal chemistry letters 2016-03, Vol.26 (6), p.1529-1535
• Main 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.
• Format: Article
• Language: English
• Subjects: Animals; Antagonist; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Dogs; Dose-Response Relationship, Drug; hERG; Humans; Mice; Molecular Structure; Rats; Receptors, Somatostatin - antagonists & inhibitors; SAR; Somatostatin receptor subtype 3; Structure-Activity Relationship; Tetrahydro-β-carboline
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.02.022

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. [Display omitted] 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.