Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

H, Ito; Imamiya, Eiko; Momose, Yū; Sugiyama, Yasuo; Kimura, Hiroyuki; Sohda, Takashi

doi:10.1248/cpb.50.1349

Cited by 18 publications

(11 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Female KK-A y mice are used for evaluation of antiobesity and antidiabetic effects of compounds and extracts, [25][26][27] since body weight over 8 weeks old is higher in female than in male. For this reason, we used female KK-A y mice in this study.…”

Section: Discussionmentioning

confidence: 99%

Licorice Flavonoids Suppress Abdominal Fat Accumulation and Increase in Blood Glucose Level in Obese Diabetic KK-Ay Mice

Nakagawa

Kishida

Arai

et al. 2004

Biological & Pharmaceutical Bulletin

123

View full text Add to dashboard Cite

Licorice, the root of the leguminous Glycyrrhiza plant species, has been used for over 4000 years since ancient Egyptian times, and is one of the most frequently employed botanicals in traditional medicines.1) There are several species of licorice, including Glycyrrhiza uralensis FISCHER, G. glabra LINNE and G. inflata BATALIN, and they include species-specific flavonoids.1,2) Our previous study showed that nonaqueous fractions of G. uralensis have peroxisome proliferator-activated receptor-g (PPAR-g) ligand-binding activity, and that the active compounds in the nonaqueous fractions are prenylflavonoids such as glycycoumarin, glycyrin, dehydroglyasperin C and dehydroglyasperin D.3,4) A licorice ethanolic extract from G. uralensis has been found to be effective in preventing and/or ameliorating diabetes, abdominal obesity and hypertension in three animal models. 3)Glabridin in G. glabra, one of the most frequently studied flavonoids of licorice, has antinephritic and radical scavenging activities, 5) exhibits inhibition of serotonin re-uptake, 6) has anti-Helicobacter pylori activity, 7) estrogen-like activity, 8) and antioxidative activity, [9][10][11][12][13][14] and inhibits melanogenesis and inflammation. 15)The metabolic syndrome is a cluster of several metabolic and cardiovascular disease risk factors including central obesity, dyslipidemia, glucose intolerance, insulin resistance and hypertension, 16) and is becoming recognized as a major public health problem. Central obesity, so-called abdominal obesity or visceral fat obesity, is believed to elicit insulin resistance, which is a major cause of the metabolic syndrome. Thiazolidinedione drugs such as troglitazone, pioglitazone and rosiglitazone, which have been approved for type 2 diabetes, 17,18) have potent PPAR-g agonistic activity and stimulate adipocyte differentiation through PPAR-g activation. 19,20) Many studies of these drugs indicate that PPAR-g agonists have significant effects on the metabolic syndrome. [21][22][23] In this study, we demonstrated the effects of licorice hydrophobic flavonoids from G. glabra on abdominal fat accumulation and blood glucose level in obese diabetic KK-A y mice, and elucidated their mechanisms of action by showing that they induce differentiation of human adipocytes. MATERIALS AND METHODS Preparation of Licorice Flavonoid Oil (LFO)The roots of licorice, Glycyrrhiza glabra LINNE, harvested in Afganistan were extracted with 5 volumes of 95% ethanol twice, and licorice ethanolic extract was obtained by filtration and concentration. The licorice ethanolic extract was dissolved in medium-chain triglycerides (MCT; C8 : C10ϭ 99 : 1; Riken Vitamin Co., Ltd., Tokyo, Japan), mixed, evaporated to remove ethanol, and filtered. The obtained oil including licorice flavonoids was used as LFO, after adjusting glabridin concentration to 1.2% (w/w) in oil. A standard for glabridin, a major compound of licorice flavonoid, was purchased from Wako Pure Chemical Inductries, Ltd. (Osaka, Japan).Animal Experiment Female genetically type 2...

show abstract

Section: Discussionmentioning

confidence: 99%

Licorice Flavonoids Suppress Abdominal Fat Accumulation and Increase in Blood Glucose Level in Obese Diabetic KK-Ay Mice

Nakagawa

Kishida

Arai

et al. 2004

Biological & Pharmaceutical Bulletin

123

View full text Add to dashboard Cite

show abstract

“…Throughout the study, they were housed in metal mesh cages and fed a commercial diet CE-2 (Clea, Japan) and water ad libitum. They were divided into 16 groups (5 rats in each group) based on plasma glucose and triglyceride, and they were intraperitoneally injected with TAK-559 (1) and its metabolites (2-5) for 7 d. Compounds (1)(2)(3)(4)(5) were suspended in 0.5% methylcellulose saline solution. TAK-559 was injected into 3 groups of rats at the doses of 0.1, 0.3 and 1.0 mg/kg/d, and each metabolite was injected into 3 groups of rats at the doses of 0.3, 1.0 and 3.0 mg/kg/d.…”

Section: Experimental Biological Procedures (A)mentioning

confidence: 99%

“…IR spectra were recorded on a JASCO IR-810. 1 H-NMR spectra were recorded on a Varian Gemini-200 spectrometer in CDCl 3 or DMSO-d 6 using tetramethylsilane as an internal standard. Chemical shifts are expressed as d (ppm) values for protons relative to the internal standard.…”

Section: Experimental Biological Procedures (A)mentioning

confidence: 99%

“…mp 111-112°C. 1 2) (9, 1.54 g, 4.95 mmol), ethyl 4-(4-hydroxyphenyl)-4-oxobutanoate (8a, 1.00 g, 4.50 mmol), acetic acid (0.773 ml, 13.5 mmol), sodium acetate (738 mg, 9.00 mmol), and ethanol (30 ml) was refluxed for 48 h, then diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel with ethyl acetate-hexane (1 : 2, v/v) to leave an oil.…”

Section: Ethyl 4-(4-methoxyphenyl)-4-oxobutanoate (7a)mentioning

confidence: 99%

See 1 more Smart Citation

Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. Preparation and Biological Activity of the Metabolites of TAK-559

Matsumoto

Odaka

et al. 2004

Chem. Pharm. Bull.

Self Cite

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor gamma (PPARg) is one of a subfamily of PPARs encoded by independent genes. Three human PPARs, designated PPARa, PPARg, and PPARd, have been identified. [3][4][5] Recent studies suggest that PPARg ligands have the ability to lower plasma glucose and triglyceride levels in insulin-resistant animal models.6) Some glucose and lipid lowering agents, which have transcriptional activity at PPARg, are currently used for clinical treatment of type 2 diabetes. 7-9)In a previous paper, we showed (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (TAK-559) (1), a novel oxyiminoalkanoic acid derivative, had strong functional activity at PPARg (Chart 1).2) TAK-559 also exhibits marked glucose and lipid lowering activities in insulin-resistant animal models, KKA y mice and Wistar fatty rats, 2,[10][11][12][13] and is under clinical trials. Metabolites M-I, M-II, M-III and M-IV were found during preclinical and clinical studies on TAK-559 (1), and their proposed structures are shown in Chart 1. To confirm the structures and to study the biological properties of the metabolites, compounds 2-5 (Charts 2-4) were synthesized and their biological activities were evaluated by both in vitro and in vivo experiments. Analytical high-performance liquid chromatography (HPLC) and mass spectroscopy (MS) of isolated metabolites (M-I, M-II, M-III, M-IV) and synthesized compounds (2-5) were shown to be identical respectively (data not shown). Transactivation activities of compounds 1-5 for human PPAR subtypes were examined using in vitro experiments, and the glucose and lipid lowering effects of the compounds were evaluated in Wistar fatty rats using in vivo experiments. The results are described below. ChemistryCompounds 2 and 3 were synthesized from commercially available 6a and 6b, respectively (Chart 2). Friedel-Crafts acylation of 6a-b gave aryl ketones 7a-b, of which the methoxy groups were converted into hydroxy groups using boron tribromide to yield 8a-b. Reactions of 8a-b with 9 2) gave aldoximes, which were hydrolyzed to afford 2 and 3.Compound 4 was prepared following the procedure described in Chart 3. The hydroxy group of compound 10 14)was protected using chloromethyl methyl ether to give 11. Lithiation at the 5-position of the oxazole 11 with n-butyllithium, followed by treatment with N,N-dimethylformamide, yielded aldehyde 12. Reduction of 12 gave the corresponding alcohol, which was protected using tert-butylchlorodiphenylsilane to yield 13. Selective removal of the methoxymethyl group of 13 was achieved using bromotrimethylsilane to give alcohol 14. Compound 14 was reacted with methanesulfonyl chloride, then coupled with 15 2) to provide 16. Removal of the tert-butyldiphenylsilyl group of 16 and subsequent hydrolysis of the ester group gave the desired compound 4.Chart 4 shows the synthesis of 5. Chloromethyloxazole 17 15) was reacted with methyl 4-hydroxybenzoate under basic conditions to yield 18. Hydrolysis of 18 gave 5 in good yield. Results...

show abstract

“…Therefore, there is a need for more effective, orally active agents, particularly Thiazolidinediones (TZDs) that normalize both glucose and insulin levels (Adisakwattana et al, 2005). Thiazolidinedione (TZD) also known as ''glitazone'', are a unique new class of oral antidiabetic agents that exert direct effects on the mechanism of insulin resistance (Imoto et al, 2002). Chemically, the members of this class are derivatives of the parent compound thiazolidinedione.…”

Section: Introductionmentioning

confidence: 99%

3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic acid alkyl ester: synthesis and antihyperglycemic evaluation

et al. 2010

View full text Add to dashboard Cite

A number of 2,4-thiazolidinedione derivatives of aryl-substituted cinnamic acid were synthesized and studied for their antihyperglycemic activity in neonatal streptozotocin-induced diabetic Wister male rats. Substitution of the aryl ring resulted in higher activity. 3-(2,4-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic acid methyl ester (Thz7), was found to be most active compound in this series which showed that disubstitutions on aryl ring by electron releasing groups were found suitable for promising antihyperglycemic activity. Increase in the ester carbon chain length decreased the activity.

show abstract

Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

Cited by 18 publications

References 42 publications

Licorice Flavonoids Suppress Abdominal Fat Accumulation and Increase in Blood Glucose Level in Obese Diabetic KK-Ay Mice

Licorice Flavonoids Suppress Abdominal Fat Accumulation and Increase in Blood Glucose Level in Obese Diabetic KK-Ay Mice

Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. Preparation and Biological Activity of the Metabolites of TAK-559

3-Aryl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic acid alkyl ester: synthesis and antihyperglycemic evaluation

Contact Info

Product

Resources

About