TIFAC CORE, JSS College of Pharmacy, Ootacamund 643001, Tamil Nadu, India; JSS Academy of Higher Education and Research (Deemed to be University), Mysuru 570015, Karnataka, India.
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund 643001, Tamil Nadu, India; JSS Academy of Higher Education and Research (Deemed to be University), Mysuru 570015, Karnataka, India.
Bioorg Chem. 2018 Apr;77:548-567. doi: 10.1016/j.bioorg.2018.02.009. Epub 2018 Feb 12.
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 The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-γ and potent insulin sensitizers.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.
噻唑烷二酮类（TZDs）或格列酮类是治疗 2 型糖尿病（T2DM）的一类重要胰岛素增敏剂。TZDs 通过抗高血糖、降血糖和降血脂作用报道具有抗糖尿病作用。随着时间的推移，这些药物被认为通过增加过氧化物酶体增殖物激活受体（PPARs）的反式激活活性而起作用。临床使用的 TZDs 存在多种严重副作用，因此后来被撤回/更新，它们是 PPAR-γ 的完全激动剂和有效的胰岛素增敏剂。这些药物是在 PPARs 的结构和机制的相关数据有限的情况下开发的。然而，近年来，PPAR-α/γ、PPAR-α/δ 和 PPAR-δ/γ 双重激动剂、PPAR 泛激动剂、选择性 PPAR-γ 调节剂和部分激动剂已经被研究。除此之外，还研究了 TZDs 的几种非 PPAR 蛋白替代物，如 FFAR1 激动剂、GPR40 激动剂和 ALR2、PTP1B 和 α-葡萄糖苷酶抑制作用，以解决与 TZDs 相关的问题。近年来，利用这些合理化方法，进行了几项研究，以开发无副作用的新型 TZDs。本报告批判性地回顾了 TZDs 的历史、化学、通过 PPAR 介导的机制、最新进展和未来前景。
