Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPARδ agonists as potential anti-diabetic agents.

Abstract:

:The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Li Z,Hu L,Wang X,Zhou Z,Deng L,Xu Y,Zhang L

doi

10.1016/j.bioorg.2019.103254

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

103254

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(19)30934-4

journal_volume

92

pub_type

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