Abstract
Preparation and biological activity of the metabolites of the potent antihyperglycemic and antihyperlipidemic agent, (E)-4-(4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (TAK-559) (1), were investigated. Metabolites M-I (2), M-II (3), M-III (4) and M-IV (5) were synthesized and their biological activities were evaluated by in vitro and in vivo experiments. Compounds 2-4 activate human peroxisome proliferator-activated receptor gamma one (hPPARgamma1) and hPPARalpha, but their activities are weaker than those of TAK-559 (1). Compound 5 only activates hPPARgamma1 weakly. TAK-559 (1) showed potent in vivo plasma glucose and triglyceride lowering activities in Wistar fatty rats after intraperitoneal administration, while its metabolites (2-5) showed comparatively weak activities.
MeSH terms
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Animals
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Biotransformation
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Blood Glucose / metabolism
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Butyrates / chemistry*
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Butyrates / metabolism
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Butyrates / pharmacology*
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COS Cells
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Chlorocebus aethiops
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Chromatography, High Pressure Liquid
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Dose-Response Relationship, Drug
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Genes, Reporter / genetics
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Humans
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / metabolism
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Hypoglycemic Agents / pharmacology*
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Injections, Intraperitoneal
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Magnetic Resonance Spectroscopy
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Male
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Mass Spectrometry
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Oxazoles / chemistry*
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Oxazoles / metabolism
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Oxazoles / pharmacology*
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Retinoic Acid / genetics
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Retinoid X Receptors
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Spectrophotometry, Infrared
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transfection
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Triglycerides / blood
Substances
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(E)-4-(4-((5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy)benzyloxyimino)-4-phenylbutyric acid
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Blood Glucose
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Butyrates
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Hypoglycemic Agents
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Oxazoles
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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Triglycerides