Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents.

Abstract

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.

• Authors: Zheng Li, Yueming Chen, Zongtao Zhou, Liming Deng, Yawen Xu, Lijun Hu, Bing Liu, Luyong Zhang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 164 Pg. 352-365 (Feb 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30605833 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Ffar1 protein, mouse
• GW 501516
• Hypoglycemic Agents
• PPAR delta
• Receptors, G-Protein-Coupled
• Thiazoles

Topics

• Animals
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Discovery
• Glucose Tolerance Test
• Hypoglycemic Agents (chemistry, pharmacokinetics, pharmacology)
• Mice
• PPAR delta (agonists)
• Receptors, G-Protein-Coupled (agonists)
• Thiazoles (chemistry, pharmacokinetics, pharmacology)