Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes. Aiming to develop potent dual PPARs/FFA1 agonists, we have hybrid the Sanofi's FFA1 agonist 1 with PPARδ agonist 2 based on their structural similarity, exemplified by the orally bioavailable FFA1/PPARγ/PPARδ pan agonist 15. [Display omitted] •A therapeutic strategy that simultaneous targets insulin secretion and resistance.•FFA1/PPARγ/PPARδ pan agonist was identified by the hybrid of FFA1 and PPARδ agonists.•Compound 15 revealed relative balanced activities between FFA1, PPARγ and PPARδ.•Compound 15 suppressed the excursion of glucose levels in a dose-dependent manner.•Compound 15 exhibited similar glucose-lowering effect as TAK-875 after 5-days treatment.