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

2004; Pharmaceutical Society of Japan; Volume: 52; Issue: 1 Linguagem: Inglês

10.1248/cpb.52.120

1347-5223

Hiroshi Imoto, Mitsuharu Matsumoto, Hiroyuki Odaka, Junichi Sakamoto, Hiroyuki Kimura, Masami Nonaka, Yutaka Kiyota, Yū Momose,

Retinoids in leukemia and cellular processes

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.