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

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

doi:10.1021/ml300063m

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

ACS Med Chem Lett. 2012 May 7;3(6):484-9. doi: 10.1021/ml300063m. eCollection 2012 Jun 14.

Authors

Shuwen He¹, Zhixiong Ye¹, Quang Truong¹, Shrenik Shah¹, Wu Du¹, Liangqin Guo¹, Peter H Dobbelaar¹, Zhong Lai¹, Jian Liu¹, Tianying Jian¹, Hongbo Qi¹, Raman K Bakshi¹, Qingmei Hong¹, James Dellureficio¹, Alexander Pasternak¹, Zhe Feng¹, Reynalda deJesus¹, Lihu Yang¹, Mikhail Reibarkh¹, Scott A Bradley¹, Mark A Holmes¹, Richard G Ball¹, Rebecca T Ruck¹, Mark A Huffman¹, Frederick Wong¹, Koppara Samuel¹, Vijay B Reddy¹, Stan Mitelman¹, Sharon X Tong¹, Gary G Chicchi¹, Kwei-Lan Tsao¹, Dorina Trusca¹, Margaret Wu¹, Qing Shao¹, Maria E Trujillo¹, George J Eiermann¹, Cai Li¹, Bei B Zhang¹, Andrew D Howard¹, Yun-Ping Zhou¹, Ravi P Nargund¹, William K Hagmann¹

Affiliation

¹ Departments of Medicinal Chemistry, Process Research, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.

Abstract

A structure-activity relationship study of the imidazolyl-β-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; β-tetrahydrocarboline.