Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.
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Accession number;03A0096290
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| Title;Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents. |
| Author;
IMOTO H
(Takeda Chemical Ind., Ltd., Osaka, Jpn)
SUGIYAMA Y
(Takeda Chemical Ind., Ltd., Osaka, Jpn)
KIMURA H
(Takeda Chemical Ind., Ltd., Osaka, Jpn)
MOMOSE Y
(Takeda Chemical Ind., Ltd., Osaka, Jpn)
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Journal Title;Chem Pharm Bull
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Journal Code:G0504A
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ISSN:0009-2363
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VOL.51;NO.2;PAGE.138-151(2003)
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| Figure&Table&Reference;FIG.1, TBL.7, REF.41 |
| Pub. Country;Japan |
| Language;English |
| Abstract;We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKAy. This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-.GAMMA.. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPAR.GAMMA.. In vivo potencies of synthesized compounds, which showed strong functional activity at PPAR.GAMMA., were tested using KKAy mice. Among these compounds, (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation. (author abst.) |
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