Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

Abstract

Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

Thiazolidinediones as leads

“…In future, benzylidene-2,4-thiazolidinedione derivatives will be utilized to improve the synthesis of new PTP-1Binhibitors. Zhang et al, (2017) has synthesized 2-thioxo-4-thiazolidinone derivatives. These derivatives were analyzed for antidiabetic activity with respect to peroxisome proliferator activated receptor gama (PPARγ) binding activity comparable with rosiglitazone.…”

Identification of Potential Therapeutic Targets in the Liver of Pioglitazone-Treated Type 2 Diabetes Sprague-Dawley Rats via Expression Profile Chip and iTRAQ Assay

“…Pioglitazone belongs to the thiazolidinedione class of drugs and was deemed as an insulin sensitizer for the therapy of T2DM [ 4 ]. As a highly selective agonist for peroxisome proliferator-activated receptor γ (PPAR- γ ), pioglitazone regulates the transcription of several genes and proteins involved in glucose and lipid metabolism [ 5 ].…”