The free fatty acid receptor 1 (FFAR1) mediates fatty acid-induced insulin secretion from pancreatic β-cells. Numerous ligands have been investigated for their antidiabetic actions. The most advanced, fasiglifam (TAK-875), is a site 1 binding agonist that stimulates IPone and improves glycemic control in diabetic patients via glucose-dependent insulin secretion (GSIS). Recently, FFAR1 agonists were discovered that bind to site 3, stimulate IPone and cAMP and result in both insulin and glucagon-like peptide-1 (GLP-1) secretion.

We hypothesized that this novel pharmacology would lead to superior glucose lowering relative to fasiglifam in diabetic monkeys. A selective FFAR1 agonist (CpdA) was discovered that activates rodent, cynomolgus and human FFAR1 receptors in vitro, triggering similar IPone and cAMP production. Incubation with CpdA but not fasiglifam restored insulin secretion in human islets from diabetic donors. Cpd A stimulates GLP-1 secretion in wild type but not GPR40 knockout mice, additionaly, as well as stimulates insulin secretion in ZDF rats. The ability of CpdA to control blood glucose was evaluated in diabetic cynomolgus monkeys during an oral glucose tolerance test after a single dose and repeated dosing for 7 days. Notably, the restoration of insulin secretion elicited by CpdA in diabetic human islets was recapitulated in vivo in diabetic monkeys and resulted in superior acute and chronic improvement in glucose tolerance relative to fasiglifam.

In conclusion, administration of CpdA restores insulin secretion and produces robust improvement in glucose metabolism in diabetic rodents and monkeys. Thus, FFAR1 agonists represent a potential treatment for type 2 diabetes.


J. Liu: None. S.P. Lee: Employee; Self; Janssen Research & Development. T. Martin: Employee; Self; Janssen Research & Development. Stock/Shareholder; Self; Janssen Research & Development. B. Rady: Employee; Self; Janssen Research & Development. S. Meegalla: None. H. Huang: None. M.P. Winters: None. L.D. Norquay: Employee; Self; Janssen Research & Development. J. Qi: None. F. Du: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.. M. Player: None. A. Pocai: None.

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