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

• Published in: Chemical & pharmaceutical bulletin Vol. 52; no. 1; pp. 120 - 124
• Main Authors: Imoto, Hiroshi, Matsumoto, Mitsuharu, Odaka, Hiroyuki, Sakamoto, Junichi, Kimura, Hiroyuki, Nonaka, Masami, Kiyota, Yutaka, Momose, Yu
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 2004; Pharmaceutical Soc Japan
• Subjects: Animals; antidiabetic agent; Biotransformation; Blood Glucose - metabolism; Butyrates - chemistry; Butyrates - metabolism; Butyrates - pharmacology; Cercopithecus aethiops; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromatography, High Pressure Liquid; COS Cells; Dose-Response Relationship, Drug; Genes, Reporter - genetics; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Injections, Intraperitoneal; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Oxazoles - chemistry; Oxazoles - metabolism; Oxazoles - pharmacology; oxyiminoalkanoic acid; peroxisome proliferator-activated receptor; Pharmacology & Pharmacy; Physical Sciences; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Retinoic Acid - genetics; Retinoid X Receptors; Science & Technology; Spectrophotometry, Infrared; TAK-559; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transfection; Triglycerides - blood; type 2 diabetes; HORMONE RECEPTOR SUPERFAMILY; ACID-DERIVATIVES; ACTIVATION; type 2 diabetes; TAK-559; PEROXISOME PROLIFERATOR; FATTY; oxyiminoalkanoic acid; peroxisome proliferator-activated receptor; antidiabetic agent; MEMBER
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.52.120

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 (hPPARγ1) and hPPARα, but their activities are weaker than those of TAK-559 (1). Compound 5 only activates hPPARγ1 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.