Although GPR119 agonists are known to stimulate insulin and incretin secretion under hyperglycemic conditions, the role of GPR119 agonism under hypoglycemic condition has not been explored. Impaired glucagon secretion is associated with insulin-induced hypoglycemia.  We evaluated whether stimulation of GPR119, a G-protein coupled receptor expressed in pancreatic islet and enteroendocrine cells, might enhance glucagon secretion during hypoglycemia. In vivo GPR119 agonists significantly increased glucagon secretion during hypoglycemia in healthy and STZ-diabetic rats.  This presentation will describe the role of lipophilicity on in vitro activity of the GPR119 agonists, the translation of in vitro potency to in vivo efficacy in preclinical models, and the impact on human dose predictions.  With this knowledge lipophilic ligand efficiency (LLE) was used to triage compounds.<br/>

Use of LLE to triage GPR119 agonists

ACS Fall 2020 Virtual Meeting

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