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

Oct 9, 2018European journal of medicinal chemistry

Design, creation, and testing of new compounds that activate three fat and metabolism-related receptors

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Abstract

Lead compound 15 demonstrated a sustained hypoglycemic effect during a 5-day treatment in ob/ob mice at a dosage of 100 mg/kg.

Lead compound 15 is a pan agonist that activates FFA1, PPARγ, and PPARδ.
The compound's effects on blood glucose levels were observed to be dose-dependent.
Comparative studies indicated that compound 15 produced effects similar to the advanced FFA1 agonist TAK-875 at a lower dosage.
The pan agonist may function by simultaneously regulating insulin secretion and resistance mechanisms.

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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.

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

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