Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. 1, 2) Preparation and Biological Activity of the Metabolites of TAK-559

• Published in: Chemical & Pharmaceutical Bulletin Vol. 52; no. 1; pp. 120 - 124
• Main Authors: Hiroshi IMOTO, Mitsuharu MATSUMOTO, Hiroyuki ODAKA, Junichi SAKAMOTO, Hiroyuki KIMURA, Masami NONAKA, Yutaka KIYOTA, Yu MOMOSE
• Format: Journal Article
• Language: Japanese
• Published: Pharmaceutical Society of Japan 2004
• ISSN: 0009-2363; 1347-5223

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 (TAK559) (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.