Discovery of gemfibrozil analogues that activate PPARα and enhance the expression of gene CPT1A involved in fatty acids catabolism

A new series of gemfibrozil analogues conjugated with α-asarone, trans-stilbene, chalcone, and their bioisosteric modifications were synthesized and evaluated to develop PPARα agonists. In this attempt, we have removed the methyls on the phenyl ring of gemfibrozil and introduced the above scaffolds in para position synthesizing two series of derivatives, keeping the dimethylpentanoic skeleton of gemfibrozil unaltered or demethylated. Four compounds exhibited good activation of the PPARα receptor and were also screened for their activity on PPARα-regulated gene CPT1A.

Graphical abstractA new series of gemfibrozil analogues conjugated with α-asarone, trans-stilbene, chalcone, and their bioisosteric modifications were synthesized and evaluated to develop PPARα agonists. Four compounds exhibited good activation of the receptor and were also screened for their activity on PPARα-regulated gene CPT1A.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of gemfibrozil conjugates with asarone, stilbene and chalcone scaffolds. ► Transactivation assay for PPARα agonistic activity. ► Preliminary structure–activity relationships discussion. ► Real-time quantitative PCR analysis: the up-regulation of CPT1A gene by stilbene derivative.