GPR40 (FFAR1) is a Class A GPCR that is highly expressed in pancreatic b-cells. Exposure to medium and long chain fatty acids, the receptor’s natural ligands, enhances glucose-dependent insulin secretion. Partial agonists of GPR40, have been shown to lower plasma glucose levels and improve HbA1c in human clinical trials, with a hypoglycemia incidence similar to that of placebo. More recently, GPR40 full agoPAMs, compounds that are both full agonists and positive allosteric modulators of the native ligands, have been shown in preclinical rat models to decrease plasma glucose to a greater extent than patial agonists. These effects are likely due to a combination of increased pancreatic insulin secretion relative to partial agonists and secretion of GLP-1 in the gut, a phenomenon not observed with partial agonists.<br/>    We have previously disclosed the discovery of a series of potent biaryl chroman GPR40 agoPAMs. A lead optimization effort was initiated which resulted in the development of compounds with excellent potency and selectivity and a low human dose projection. A select compound from this series was further profiled and this presentation will describe in vivo efficacy studies including a wild type and GPR40 knock out mouse ipGTT to assess on target efficacy and a Goto-Kakizaki rat PK/PD study to evaluate effects on glucose, insulin and incretin levels. Projection of a low human dose based on translation from in vitro potency and in vivo efficacy results will also be discussed.

Design of a potent and selective GPR40 agoPAM with low projected human dose

256th National Meeting (2018)

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