Thiazolidinediones as antidiabetic agents: A critical review

[Display omitted] •Thiazolidinediones (TZDs) or glitazones are an important class of drugs used in type 2 diabetes mellitus (T2DM).•TZDs are known to act by modulation of peroxisome proliferators activated receptors (PPARs).•The historical aspects and the mode of action of TZDs are described.•The chemistry of TZDs as antihyperglycemic agents, hypoglycemic and hypolipidemic dual agents are reviewed.•TZDs as PPAR, FFAR1 and GPR40 agonists and inhibitors of ALR2, PTP1B and α-glucosidase are also described. Thiazolidinediones (TZDs) or Glitazones are an important class of insulin sensitizers used in the treatment of Type 2 diabetes mellitus (T2DM). TZDs were reported for their antidiabetic effect through antihyperglycemic, hypoglycemic and hypolipidemic agents. In time, these drugs were known to act by increasing the transactivation activity of Peroxisome Proliferators Activated Receptors (PPARs). The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-γ and potent insulin sensitizers. These drugs were developed at a time when limited data were available on the structure and mechanism of PPARs. In recent years, however, PPAR-α/γ, PPAR-α/δ and PPAR-δ/γ dual agonists, PPAR pan agonists, selective PPAR-γ modulators and partial agonists have been investigated. In addition to these, several non PPAR protein alternatives of TZDs such as FFAR1 agonism, GPR40 agonism and ALR2, PTP1B and α-glucosidase inhibition have been investigated to address the problems associated with the TZDs. Using these rationalized approaches, several investigations have been carried out in recent years to develop newer TZDs devoid of side effects. This report critically reviews TZDs, their history, chemistry, mechanism mediated through PPAR, recent advances and future prospects.