Virtual Screening, Docking, Synthesis and Bioactivity Evaluation of Thiazolidinediones as Potential PPARγ Partial Agonists for Preparation of Antidiabetic Agents

Abstract

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the key targets of insulin resistance research, in addition to being ligand-activated transcription factors of the nuclear hormone receptor superfamily with a leading role in adiposeness activation and insulin sensitivity. They regulate cholesterol and carbohydrate metabolism through direct actions on gene expression. Despite their therapeutic importance, there are dose limiting side effects associated with PPARγ drug treatments, thus a new generation of safer PPARγ drugs are being actively sought after treatment. Methods: In this study, we used computer aided drug design to screen new series of PPARγ ligands, and synthesized a series of potential thiazolidinedione derivatives such as 5,7- dibenzyloxybenzyl-3-hydroxymethyl-4H-coumarin-4-ketone, using 4-steps to synthesize the target compounds and built streptozotocin (STZ) induced insulin resistance rat model to measure their antidiabetic activity. Results: We found that 10 mg/kg concentration of compound 0701C could significantly decrease blood glucose and serum PPARγ, serum insulin levels in insulin resistance model rat. Conclusion: We would conclude that compound 0701C might serve as a potential PPARγ partial agonist.

<p>The Role of JNk Signaling Pathway in Obesity-Driven Insulin Resistance</p>

“…There are so many researches indicating that PPARγ plays a central role in adipocyte differentiation, sugar and lipid metabolism, inflammatory response, atherosclerosis, and the improvement of insulin resistance. 26,27 PPARγ ligands inhibit the expression of various inflammation-related genes, including inducible nitric oxide synthase, matrix metalloproteinases, and interleukins. These behaviors may also be associated with obesity-related insulin resistance, because macrophage accumulation and gene expression in adipose tissue have been proven to play an important role in the pathogenesis of obesity-driven insulin resistance.…”