Elsevier

Bioorganic Chemistry

Volume 77, April 2018, Pages 548-567
Bioorganic Chemistry

Review article
Thiazolidinediones as antidiabetic agents: A critical review

https://doi.org/10.1016/j.bioorg.2018.02.009Get rights and content

Highlights

Abstract

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 The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-γ and potent insulin sensitizers.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.

Introduction

Diabetes mellitus (DM) is a metabolic disorder, characterized by hyperglycemia and related problems caused due to deficiency in insulin secretion, insulin action or both in combination. Type 1 diabetes mellitus (T1DM) is associated with lack of insulin, either completely or partially, due to autoimmune-mediated destruction of pancreatic β-cells, whereas type 2 diabetes mellitus (T2DM) is correlated with erratic degrees of insulin resistance, imbalanced insulin secretion, moderate to severe beta-cell apoptosis and increased hepatic glucose production [1]. The hormonal balance of insulin and glucagon sustain glucose homeostasis by controlling its concentration in the blood. An increase in the blood glucose level triggers insulin mediated signaling to lower the raised levels by increasing glucose uptake in the skeletal muscle, adipocytes and kidneys along with the promotion of its utilization and storage in the liver. When the blood glucose level decreases, glucagon acts to promote glucose production and release in the liver and by increasing lipolysis from adipose tissue. Glucose homeostasis can also be influenced by compounds that target glucose regulating processes in the pancreas, liver, skeletal muscles and adipocytes [2]. The conventional pharmaceutical agents used in the treatment of DM include insulin and oral antidiabetic agents such as sulphonylureas, biguanides, thiazolidinediones (TZDs) and γ-glucosidase inhibitors [3].

Section snippets

Historical aspects of TZDs

In early 1975, Japanese based Takeda laboratories synthesized 71 analogues of Clofibrate, in an attempt to discover more potent fibrate hypolipidemic drugs and tested them for their hypolipidemic activity [4]. Interestingly some of these compounds displayed hypoglycemic effects in diabetic mice (Fig. 1). In the year 1982, through extensive studies on structure-activity relationship, the first TZD, Ciglitazone, was discovered with promising lipid and glucose lowering effects in animal models.

Advantages of TZDs

The primary purpose of TZDs is to control hyperglycemia in T2DM patients by lowering the fasting blood glucose levels to normal levels (<100 mg/dL) and reducing the concentration of HbA1c, the glycosylated form of hemoglobin. Higher levels of HbA1c indicate long-term exposure to elevated levels of blood glucose. This is in contrast to an instant measure of glucose, which indicates a “snapshot” of blood sugar levels. Both Rosiglitazone and Pioglitazone act similar in improving glucose levels,

Mechanism of action of TZDs

The molecular mechanisms of biological responses of TZDs are reported to be mediated through the modulation of PPARs [17]. These nuclear receptors identified in mouse in the year 1990 [18], are reported to be activated upon exposure to peroxisome proliferators, such as hypolipidemic drugs, herbicides and industrial plasticizers. In 1992, three isotypes of PPARs, namely, PPAR-α (NR1C1), PPAR-β/δ (NR1C2) and PPAR-γ (NR1C3) in xenopus were reported [19]. PPARs are transcription factors that can be

PPAR based ligands

The structural similarity of PPAR-α, -γ and -δ, particularly in their ligand-binding domains, has rationalized the development/exploration of several synthetic/natural dual- or pan-PPAR agonists. Several reviews have also been reported based on various structural aspects of PPAR receptor [31], [32], [33], [34]. Molecules that display balanced activation (dual agonists) have been hypothesized to provide a better balance between efficacy and side effects when compared to single agonists or dual

TZDs as agents for T2DM

The TZDs which are withdrawn from the clinical use were developed at the time when not much scientific data were available on the structure and the transcriptional mechanisms of PPARs. Recent advances in the understanding of the structure and function of PPARs have led to newer and more rationalized approaches to develop agents of this class. Recent reviews on TZDs as antidiabetic agents have led to a better understanding of the different aspects of their medicinal chemistry [40], [41], [42].

Summary and future perspectives

TZDs are an important class of drugs that act by increasing the transactivation activity of PPARs, as a result of which, they reduce hepatic glucose production, increase peripheral utilization of glucose and lipid metabolism. These actions, therefore, reduce the preload and after load on β-cells and lipid homeostasis. As a result, the effect of endogenous insulin improves so as to maintain the level of blood glucose. Unfortunately, the clinically used TZDs, Troglitazone, Pioglitazone and

References (102)

  • J.H. Lee et al.

    Kinetics of the absorption, distribution, metabolism, and excretion of lobeglitazone, a novel activator of peroxisome proliferator-activated receptor gamma in rats

    J. Pharm. Sci.

    (2015)
  • S. Yasmin et al.

    Thiazolidinediones and PPAR orchestra as antidiabetic agents: from past to present

    Eur. J. Med. Chem.

    (2017)
  • M.J. Naim et al.

    Therapeutic journey of 2,4-thiazolidinediones as a versatile scaffold: An insight into structure activity relationship

    Eur. J. Med. Chem.

    (2017)
  • B. Hulin et al.

    Synthesis of a biotin conjugate of darglitazone, a new antidiabetic agent. A general protocol for the reversible biotinylation of ketones

    Bioorg. Med. Chem. Lett.

    (1993)
  • B.R. Prashantha Kumar et al.

    Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships

    Bioorg. Chem.

    (2012)
  • G.R. Madhavan et al.

    Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents

    Eur. J. Med. Chem.

    (2001)
  • G.R. Madhavan et al.

    Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives

    Bioorg. Med. Chem.

    (2002)
  • B.Y. Kim et al.

    Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione

    Eur. J. Med. Chem.

    (2004)
  • H.W. Lee et al.

    Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione

    Eur. J. Med. Chem.

    (2005)
  • D. Gupta et al.

    Synthesis and pharmacological evaluation of substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene] thiazolidine-2,4-dione derivatives as potent euglycemic and hypolipidemic agents

    Bioorg. Med. Chem. Lett.

    (2005)
  • A.K. Mohammed Iqbal et al.

    Synthesis, hypoglycemic and hypolipidemic activities of novel thiazolidinedione derivatives containing thiazole/triazole/oxadiazole ring

    Eur. J. Med. Chem.

    (2012)
  • B.G. Shearer et al.

    The next generation of PPAR drugs: do we have the tools to find them?

    Biochim. Biophys. Acta.

    (2007)
  • C. Fiévet et al.

    PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome

    Curr. Opin. Pharmacol.

    (2006)
  • N. Kubota et al.

    PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance

    Mol. Cell.

    (1999)
  • H. Koyama et al.

    5-Aryl thiazolidine-2,4-diones as selective PPAR-γ agonists

    Bioorganic Med. Chem. Lett.

    (2003)
  • R.C. Desai et al.

    5-Aryl thiazolidine-2,4-diones: discovery of PPAR dual α/γ agonists as antidiabetic agents

    Bioorg. Med. Chem. Lett.

    (2003)
  • S. Nazreen et al.

    Thiazolidine-2,4-diones derivatives as PPAR-γ agonists: Synthesis, molecular docking, in vitro and in vivo antidiabetic activity with hepatotoxicity risk evaluation and effect on PPAR-γ gene expression

    Bioorg. Med. Chem. Lett.

    (2014)
  • S. Nazreen et al.

    Design, synthesis, in silico molecular docking and biological evaluation of novel oxadiazole based thiazolidine-2,4-diones bis-heterocycles as PPAR-γ agonists

    Eur J. Med. Chem.

    (2014)
  • A.K. Jain et al.

    Recent developments and biological activities of thiazolidinone derivatives: a review

    Bioorg. Med. Chem.

    (2012)
  • G. Bruno et al.

    Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones

    Bioorg. Med. Chem.

    (2002)
  • R. Ottanà et al.

    Identi fi cation of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications

    Eur. J. Med. Chem.

    (2011)
  • D. Rakowitz et al.

    In vitro aldose reductase inhibitory activity of 5-benzyl-2,4-thiazolidinediones

    Bioorg. Med. Chem.

    (2006)
  • O. Bozdağ-Dündar et al.

    Synthesis and aldose reductase inhibitory activity of some new chromonyl-2,4-thiazolidinediones

    Eur. J. Med. Chem.

    (2008)
  • O. Bozdağ-Dündar et al.

    Synthesis and biological activity of some new flavonyl-2,4-thiazolidinediones

    Bioorg. Med. Chem.

    (2008)
  • R. Ottanà et al.

    5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors

    Bioorg. Med. Chem.

    (2009)
  • R. Maccari et al.

    5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases

    Bioorg. Med. Chem.

    (2007)
  • B.R. Bhattarai et al.

    Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects

    Bioorg. Med. Chem. Lett.

    (2009)
  • B.R. Bhattarai et al.

    Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as PTP1B inhibitors and PPAR-γ activators

    Bioorg. Med. Chem. Lett.

    (2010)
  • Z. Wang et al.

    Design, synthesis and docking study of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as inhibitors of protein tyrosine phosphatase 1B

    Bioorg. Med. Chem. Lett.

    (2014)
  • Y. Chinthala et al.

    Synthesis, biological evaluation and molecular modeling studies of some novel thiazolidinediones with triazole ring

    Eur. J. Med. Chem.

    (2013)
  • T. Hara et al.

    Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders

    J. Pharm. Sci.

    (2011)
  • K.M. Darwish et al.

    Design, synthesis, and biological evaluation of novel thiazolidinediones as PPARγ/FFAR1 dual agonists

    Eur. J. Med. Chem.

    (2016)
  • P. Zimmet et al.

    Global and societal implications of the diabetes epidemic

    Nature.

    (2001)
  • R.J. Jha

    Thiazolidinediones–the new insulin enhancers

    Clin. Exp. Hypertens.

    (1999)
  • H.R. Saleh

    YM, Mudaliar SR, Metabolic and vascular effects of the thiazolidinedione troglitazone

    Diabetes Rev.

    (1999)
  • K.Y. Sohda

    T, Mizuno K, Imamiya E, Sugiyama Y, Fujita T, Studies on Antidiabetic Agents II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives

    Chem. Pharm. Bull.

    (1982)
  • F. Lalloyer et al.

    Fibrates, glitazones, and peroxisome proliferator-activated receptors

    Arterioscler. Thromb. Vasc. Biol.

    (2010)
  • S.E. Nissen

    The rise and fall of rosiglitazone

    Eur. Heart J.

    (2010)
  • J. Woodcock et al.

    Regulatory action on rosiglitazone by the U.S. Food and Drug Administration

    N. Engl. J. Med.

    (2010)
  • C.J. Rosen

    Revisiting the rosiglitazone story–lessons learned

    N. Engl. J. Med.

    (2010)
  • Cited by (213)

    View all citing articles on Scopus
    View full text