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ACS Med Chem Lett. 2012 Feb 27;3(4):289-93. doi: 10.1021/ml200272z. eCollection 2012 Apr 12.

Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist.

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Merck Research Laboratories , Rahway, New Jersey 07065, United States.


This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.


glucose-stimulated insulin secretion; somatostatin; sst3; type 2 diabetes

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