The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

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• 作者：Shuwen He ; Zhixiong Ye ; Quang Truong ; Shrenik Shah ; Wu Du ; Liangqin Guo ; Peter H. Dobbelaar ; Zhong Lai ; Jian Liu ; Tianying Jian ; Hongbo Qi ; Raman K. Bakshi ; Qingmei Hong ; James Dellureficio ; Alexander Pasternak ; Zhe Feng ; Reynalda deJesus ; Lihu Yang ; Mikhail Reibarkh ; Scott A. Bradley ; Mark A. Holmes ; Richard G. Ball ; Rebecca T. Ruck ; Mark A. Huffman ; Frederick Wong ; 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 ; George J. Eiermann ; Cai Li ; Bei B. Zhang ; Andrew D. Howard ; Yun-Ping Zhou ; Ravi P. Nargund ; William K. Hagmann
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：3
• 期：6
• 页码：484-489
• 全文大小：336K
• 年卷期：v.3,no.6(June 14, 2012)
• ISSN：1948-5875

文摘

A structure鈥揳ctivity relationship study of the imidazolyl-尾-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

Keywords:

SSTR3; antagonist; type 2 diabetes; 尾-tetrahydrocarboline