Thiazolidinediones compounds

A wide spectrum of thiazolidinedione compounds have been synthesized and characterized over the past 15 years. In general, these compounds were shown to be active in obese rodent models of type 2 diabetes but were not active in insulin-deficient diabetes, as in streptozo-tocin-treated rats. Thus, the compounds were shown to be insulin sensitizers with little or no potential to evoke hypoglycemia. In addition to potent insulin-sensitizing and glucose-lowering effects, the thiazolidinediones also showed substantial efficacy with respect to hypertriglyceridemia in animal models. A small number of thiazolidinediones have... 

Two thiazolidinedione compounds that contain the pyridine ring and that are used for diabetes are pioglitazone (the hydrochloride salt is sold by Takeda Pharmaceuticals Inc. as ACTOS) and rosiglitazone (sold as the maleate by GlaxoSmithKhne as AVANDIA). 

The members of this class are derivatives of the parent compound thiazolidinedione, and include rosiglitazone, pioglitazone and troglitazone which was withdrawn from the market due to an increased incidence of drug-induced hepatitis. 

The 3,4-dihydro-22/-l,3-benzoxazin-4-one derivative DRF-2519 587, bearing a 2,4-thiazolidinedione moiety in the side chain attached to the nitrogen atom, proved to be an activator of the a- and y-types of the peroxisome proliferator-activated receptors (PPAR-a and -7), which endowed it with antidiabetic and hypolipidemic potential. Compound 587 demonstrated significant plasma glucose-, insulin-, and lipid-lowering activity in mice and improvement in lipid parameters in fat-fed rats <2006BMC584>. 

Two thiazolidinediones are currently available pioglitazone and rosiglitazone (Table 41-8). Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. An earlier compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain. 

Table I shows the structures and PPARy binding potency of selected thiazolidinedione and synthetic nonthiazolidinedione compounds.

The chemistry of 4-thiazolidinones (1) was reviewed in depth by Brown in 1962.1 Since then, largely due to the wide variety of physiological activity demonstrated by this class of compounds, several thousand papers2 on the chemistry of 4-thiazolidinone derivatives, exclusive of rhodanine derivatives, have been published. This review will consider only the important literature highlights of 1, 2,4-thiazolidinediones (2), 2-imino-4-thiazolidinones (3), and 4-oxo-2-thiazolin-2-ylhydrazones (4). Neither rhodanine (5) nor the extensive patent and obscure literature references dealing with 4-thiazolidinones will be considered in any detail within this review. 

The thiazolidinedione group can be replaced by other acidic heterocycles. Oxazolidinediones such as (44) can achieve high potency [230]. In the ob/ob mouse (44) normalized blood glucose at 0.5 mg/kg. The thiazolidinedione can also be replaced by an oxathiadiazole oxide. The 2-naphthyl compound (45), analogous to the sulphonyl thiazolidinedione (41), was the most active compound of the series, ca. 5 times as potent as ciglitazone [231]. 

Thiazolidinediones (e.g., rosiglitazone 4) reduce insulin resistance (insuhn sensitizers). These compounds stimulate peroxisome-proliferator-activated receptors (PPARs) on the nuclear surface, leading to increased glucose uptake and reduced hepatic gluconeogenesis [50]. 

Figure 1.4. Common structural features found in thiazolidinedione PPARy agonists and related compounds.

Troglitazone (( )-5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yhnethoxy) benzyl]-2,4-thiazolidinedione) is an oral insulin sensitizer belonging to the thiazolidinedione class of compounds used for the treatment of type II diabetes. Its withdrawal from the US market was the consequence of the recent occurrence of hepatic failure leading sometimes to death. 

Left two representatives of two groups of orally applied anti-diabetic drugs. Compound 1 derives from sulfonylurea and 2 from thiazolidinedione. Right schematic drawing of the hormone insulin. The active form, a monomer (shown), consists of two peptide chains which are hnked by two disulfide bridges. Chain A contains an additional disulfide hnk. 

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