Abstract
Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes.
Highlights
Diabetes Mellitus is one of the major threats to human health worldwide and it will be the seventh leading cause of death in 2030 [1]
A report by WHO is of high concern that the number of people above eighteen years of age getting affected by diabetes has rapidly increased [2]
Range of drugs like sulfonylureas, biguanides, glinides, and glitazones are used for the treatment of type 2 diabetes but all of them suffer from unintended effects like hypoglycemia and obesity [3,4,5,6]
Summary
Diabetes Mellitus is one of the major threats to human health worldwide and it will be the seventh leading cause of death in 2030 [1]. Thiazolidinediones (TZDs) or glitazones are important group of drugs which are active orally in the treatment of type 2 diabetes. TZDs bind avidly to Peroxisome proliferator-activated receptor gamma (PPARγ agonists) and the activation of PPARγ by these drugs influences a number of genes expressed which are involved in lipid and glucose metabolism and preadipocyte differentiation. They enhance the sensitivity to insulin (insulin sensitizers) and promote the utilization of glucose by peripheral tissues [7]. Understanding the structure of PPAR as the molecular target for thiazolidinediones, its functions in glucose and lipid metabolism, and nature of the binding interactions between PPAR and their agonists are indispensable for the discovery and design of new antidiabetic drugs. We have attempted to delineate the structure of thiazolidinediones that is vital for the development of generation PPARγ or PPARα/γ agonists to be used in the treatment of type 2 diabetes
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