Synthesis and evaluation of new 1,2,4-oxadiazole based trans- acrylic acid derivatives as potential PPAR-alpha/gamma dual agonist.

Abstract

Diabetes is a ubiquitously a metabolic disorder and life-threatening disease. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors which acts as transcription factors to regulate lipid and glucose metabolism. PPAR alpha/gamma dual agonists tend to corroborate the functions of both thiazolidinediones and fibrates and they hold substantial promise for ameliorating the type 2 diabetic treatments and providing potential therapeutic diabetic interventions. New 1,2,4-oxadiazole based trans- acrylic acid derivatives compounds possessing aryl/methylene linker in between pharmacophore head and lipophilic tail for dual PPAR-alpha/gamma agonists are studied. AutoDock Vina used for potential PPAR alpha/gamma dual agonists and 6 compounds 9a, 9g, 9m, 9n, 9o, and 9r were identified comparable to PPAR gamma agonist Pioglitazone on the basis of their affinity scores and further their in-silico toxicity and in-silico ADME properties. The selected compounds showed better-calculated lipophilicity (iLogP) was found to be 0.92 to 3.19. Compound 9n and 9a were found to be most potent on both PPAR alpha and gamma receptors with EC50 of 0.07±0.0006µM, 0.06±0.0005µM and 0.781±0.008µM, 3.29µM±0.03 respectively as better to pioglitazone having EC50 of 32.38±0.2 and 38.03±0.13 for both receptors. The in-vivo evaluation found to reduce the plasma glucose level and total cholesterol level significantly in diabetic rats compared to pioglitazone at 5mg/kg/day dose for 7days of treatment. Thus, trans- acrylic acid derivatives can be further developed as oral therapeutic agents for diabetic interventions as PPAR alpha/gamma dual agonists.