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
  • 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.
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