Heterocyclyl linked a- alkoxy carboxylic acids as novel antidiabetic agents: design synthesis and computational validation studies

Abstract

The discovery of the crucial role of Peroxisome Proliferator Activated Receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tool for therapeutic intervention in type 2 diabetes mellitus (T2DM) and metabolic syndrome. newlineAn important class of compounds currently under focus in the same category is dual activators of Peroxisome Proliferator Activated Receptors (,). Each of these subtypes appears to be differentiated in a tissue-specific manner and to play a pivotal role in glucose and lipid homeostasis. Special efforts to design multiple activating molecules can be successfully made using computational methods. Knowledge of the 3D structure of all the targeted receptors is of an advantage. PPAR agonists enhance insulin action and promote glucose utilization in peripheral tissues. PPAR agonists improve insulin sensitivity associated with obesity and mediate their effects on lipid metabolism. Therefore PPAR/ dual activators provide superior profile toward the control of hyperglycemia and hypertriglyceridemia. So, we first aimed to work on the hypothesis that PPAR/ dual agonism must provide additive and positive synergistic pharmacology, and laid down certain objectives to meet and fulfill the issues facing the development of dual activating agonists: a balance between and activity. newlineThe fact that dual PPARand#945;/and#947; activators though highly potent agonists of PPARand#945; and and#947;; they lead to various undesirable adverse effects (cardiovascular, hepatic, carcinogenic etc.) came into picture in the due course of time during the research work. Partial agonism simultaneously to both the Receptors may provide solution to the problem of toxic adverse effects of dual activators. newlineWe accordingly planned to synthesize and validate computationally heterocyclyl linked acyclic analogs of oxazolidinediones i.e. and#945;-alkoxy propanoic acids, as was designed on the basis of 3D-QSAR studies, having almost all the structural features to act