ChemInform Abstract: Studies on Antidiabetic Agents. Synthesis and Hypoglycemic Activity of 5‐(4‐(Pyridylalkoxy)benzyl)‐2,4‐thiazolidinediones.

Sohda, Takashi; Momose, Yū; Meguro, Kanji; Kawamatsu, Yutaka; Sugiyama, Yasuo; Ikeda, Hitoshi

doi:10.1002/chin.199023199

Cited by 45 publications

(52 citation statements)

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“…All of the TZDs were synthesized at Nippon Chemiphar (Misato, Japan). Troglitazone, pioglitazone-HCl (pioglitazone), and BRL-49653 were synthesized as previously described (20)(21)(22). NC-2100 {[±]-5-[(7-benzyloxy-3-quinolyl)methyl]-2,4-thiazolidinedione} was synthesized using methods described in Patent Cooperation Treaty patent WO-9612719.…”

Section: Methodsmentioning

confidence: 99%

A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

et al. 2000

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Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.

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Section: Methodsmentioning

confidence: 99%

A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

et al. 2000

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“…This compound is a selective PPARγ agonist and weak PPARα agonist which improves hyperlipidemia and hyperglycemia in obese and diabetic animals. [9][10][11] It has also been shown to inhibit the growth of human hepatocellular carcinomas, and esophageal squamous, gastric and pancreatic cancer cells in vitro. [12][13][14][15] In addition, pioglitazone and another PPARγ agonist, troglitazone, are reported to suppress formation of dextran sodium sulfate (DSS)/ azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the rat colon.…”

mentioning

confidence: 99%

Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

Niho¹,

Takahashi²,

Shoji³

et al. 2003

Cancer Science

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In our previous study, a peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc 1309 mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPARγ γ γ γ agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPARγ γ γ γ agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer. onsumption of a high fat diet is epidemiologically related to the risk of colon cancer.

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“…Thus, condensation of 3 with o-phenylenediamine (13) and 4-(chlorophenyl)-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (14) 23 3 , H enone and H-5 thiadiazepine , respectively. The reaction of 3 with 1,4-binucleophiles proceeds via γ-pyrone ring opening followed by an intramolecular condensation reaction to effect cyclization leading to seven membered ring systems.…”

Section: Resultsmentioning

confidence: 99%

“…2 2,4-TZDs differ markedly from other antidiabetic drugs in that they are effective in normalizing glucose and lipid metabolism associated with insulin resistance and therefore are expected to be useful in treatment of type 2 diabetes mellitus and obesity. [3][4][5] Besides, it was reported that some 2,4-TZDs have been used as antihyperglycemic 6 and aldose reductase (AR) inhibitory agents with dual activity. 7 There is a great interest in 2,4-TZD derivatives as aldose reductase inhibitors (ARIs), 7,8 since they can be viewed as hydantoin bioisosters potentially free of the hypersensitivity reactions which are linked to the presence of the hydantoin system.…”

Section: Introductionmentioning

confidence: 99%

A new approach for the synthesis of bioactive heteroaryl thiazolidine-2,4-diones

Ibrahim¹,

Abdel-Hamed²,

El-Gohary³

2011

J. Braz. Chem. Soc.

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A condensação do 3-formilcromano (1) com tiazolidina-2,4-diona (2) produziu 5-[4-oxo-4H-croman-3-ila)metileno]-1,3-tiazolidina-2,4-diona (3). A reação de 3 com hidrato de hidrazina, fenil hidrazina e hidrocloreto de hidroxilamina produziu os derivados correspondentes pirazol e isoxazol 4-7. O composto 3 reagiu com tiouréia, guanidina e cianoguanidina para produzir os derivados correspondentes de pirimidina 8-10. Pirimido

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ChemInform Abstract: Studies on Antidiabetic Agents. Synthesis and Hypoglycemic Activity of 5‐(4‐(Pyridylalkoxy)benzyl)‐2,4‐thiazolidinediones.

Abstract: The pyridylethanols (I) are transformed into the p‐nitrophenyl ethers (III) which undergo coupling with the acrylate (IV) via reduction and diazotization to form the pyridylethoxyphenylpropionates (V).

Cited by 45 publications

References 0 publications

A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

A new approach for the synthesis of bioactive heteroaryl thiazolidine-2,4-diones

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