The Prostaglandin EP3 receptor is a 7-transmembrane G-protein coupled receptor found in a variety of human tissues including the kidney, uterus, bladder, stomach, brain, and pancreas. Prostaglandin E2 (PGE2), a primary product of arachidonic acid metabolism by the cyclooxygenase pathway, is the natural ligand which activates EP3 as well as other EP receptor subtypes. Recent studies have provided strong evidence underscoring the role of increased levels of PGE2 contributing to defective insulin secretion in diabetic patients. Animal models have demonstrated that PGE2 suppression of glucose-stimulated insulin secretion (GSIS) operates through the EP3 receptor. It is hypothesized that increased PGE2 signaling through the EP3 receptor might also help drive the development of diabetes and contribute to β-cell dysfunction. Therefore, EP3 receptor antagonists may be an effective treatment for type 2 diabetes by relieving the inhibitory action of PGE2 to partially restore defective GSIS in diabetic patients.<br/>Herein we report our discovery of a novel series of potent heterocycles EP3 antagonists. We describe an extensive medicinal chemistry campaign to identify a lead compound with potent hEP3 binding affinity and functional activity, good physical properties, an excellent PK profile, and promising <i>in vivo</i> efficacy as a pre-clinical candidate for the treatment of type 2 diabetes.

Discovery of a novel series of heterocycles as potent EP3 antagonists for the treatment of type 2 diabetes

254th National Meeting (2017)

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