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

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.
Shuwen He 1 Zhixiong Ye 1 Quang Truong 1 Shrenik Shah 1 Wu Du 1 Liangqin Guo 1 Peter H Dobbelaar 1 Zhong Lai 1 Jian Liu 1 Tianying Jian 1 Hongbo Qi 1 Raman K Bakshi 1 Qingmei Hong 1 James Dellureficio 1 Alexander Pasternak 1 Zhe Feng 1 Reynalda deJesus 1 Lihu Yang 1 Mikhail Reibarkh 1 Scott A Bradley 1 Mark A Holmes 1 Richard G Ball 1 Rebecca T Ruck 1 Mark A Huffman 1 Frederick Wong 1 Koppara Samuel 1 Vijay B Reddy 1 Stan Mitelman 1 Sharon X Tong 1 Gary G Chicchi 1 Kwei-Lan Tsao 1 Dorina Trusca 1 Margaret Wu 1 Qing Shao 1 Maria E Trujillo 1 George J Eiermann 1 Cai Li 1 Bei B Zhang 1 Andrew D Howard 1 Yun-Ping Zhou 1 Ravi P Nargund 1 William K Hagmann 1
Affiliations

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.

Figures
Products