GPR40 is a G-protein coupled receptor expressed primarily in pancreatic b-cells that has been a target of significant interest for type 2 diabetes. Activation of GPR40 by its endogenous ligands (medium and long chain fatty acids) results in exocytosis of insulin granules only in the presence of elevated blood glucose, mitigating risk of hypoglycemia. To date, all GPR40 compounds that have been assessed in a clinical setting operate by partial activation of the receptor. In recent years, multiple groups reported GPR40 compounds that operate as full agonists with positive allosteric modulation (PAM) of the endogenous ligands resulting in enhanced glucose lowering in vivo. In this presentation, the discovery and optimization of a series of potent, selective GPR40 full agonists will be discussed. In vivo profiling of lead compounds and preclinical DILI de-risking resulted in the identification of two compounds suitable for clinical development in man. However, observation of mechanism-based induction of irreversible hyperglycemia in rodents resulted in re-prioritization of GPR40 full agonism as a potential therapy for diabetic patients.

Identification and optimization of positive allosteric GPR40 agonists for diabetes

ACS Spring Meeting 2021

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