Type 2 diabetes mellitus (T2DM) has become a worldwide epidemic, causing significant morbidity and mortality.  We have focused on the development of novel agents that promote glucose-dependent insulin secretion (GDIS) from pancreatic �-cells, thus minimizing hypoglycemia risk. Somatostatin inhibits the release of growth hormone from the anterior pituitary. Somatostain also suppresses the production of the pancreatic hormones (e.g., insulin and glucagon), has a role in central nervous system as a neurotransmitter, is involved in the regulation of gastric secretion, and may regulate cell proliferation. The functions of somatostatin are mediated through five G-protein coupled receptors (SSTR1 to SSTR5). We had found that antagonism of a subtype of SSTR has the potential to be a novel GDIS mechanism for the treatment of T2DM.  We will discuss the SAR effort that led to the discovery of MK-4256,  a potent subtype selective SSTR antagonist, which demonstrated superior efficacy in a mouse oGTT model.

Discovery of MK-4256, a subtype selective SSTR antagonist as a potential treatment of type-2 diabetes

243rd National Meeting (2012)

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