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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