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Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

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journal contribution
posted on 10.07.2014, 00:00 by Shuwen He, Zhong Lai, Zhixiong Ye, Peter H. Dobbelaar, Shrenik K. Shah, Quang Truong, Wu Du, Liangqin Guo, Jian Liu, Tianying Jian, Hongbo Qi, Raman K. Bakshi, Qingmei Hong, James Dellureficio, Mikhail Reibarkh, Koppara Samuel, Vijay B. Reddy, Stan Mitelman, Sharon X. Tong, Gary G. Chicchi, Kwei-Lan Tsao, Dorina Trusca, Margaret Wu, Qing Shao, Maria E. Trujillo, Guillermo Fernandez, Donald Nelson, Patricia Bunting, Janet Kerr, Patrick Fitzgerald, Pierre Morissette, Sylvia Volksdorf, George J. Eiermann, Cai Li, Bei Zhang, Andrew D. Howard, Yun-Ping Zhou, Ravi P. Nargund, William K. Hagmann
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.