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
Author Information
Shuwen He: 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.
Zhixiong Ye: 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.
Quang Truong: 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.
Shrenik Shah: 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.
Wu Du: 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.
Liangqin Guo: 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.
Peter H Dobbelaar: 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.
Zhong Lai: 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.
Jian Liu: 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.
Tianying Jian: 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.
Hongbo Qi: 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.
Raman K Bakshi: 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.
Qingmei Hong: 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.
James Dellureficio: 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.
Alexander Pasternak: 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.
Zhe Feng: 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.
Reynalda deJesus: 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.
Lihu Yang: 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.
Mikhail Reibarkh: 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.
Scott A Bradley: 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.
Mark A Holmes: 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.
Richard G Ball: 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.
Rebecca T Ruck: 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.
Mark A Huffman: 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.
Frederick Wong: 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.
Koppara Samuel: 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.
Vijay B Reddy: 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.
Stan Mitelman: 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.
Sharon X Tong: 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.
Gary G Chicchi: 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.
Kwei-Lan Tsao: 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.
Dorina Trusca: 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.
Margaret Wu: 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.
Qing Shao: 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.
Maria E Trujillo: 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.
George J Eiermann: 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.
Cai Li: 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.
Bei B Zhang: 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.
Andrew D Howard: 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.
Yun-Ping Zhou: 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.
Ravi P Nargund: 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.
William K Hagmann: 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.
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.
