Studies on non-thiazolidinedione antidiabetic agents. 3. Preparation and biological activity of the metabolites of TAK-559.
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.
Imoto
Hiroshi
H
Pharmaceutical Research Division, Takeda Chemical Industries Ltd., 2-17-85 Juso-Honmachi, Yodogawa-ku, Osaka 532-8686, Japan. Imoto_Hiroshi@takeda.co.jp
Matsumoto
Mitsuharu
M
Odaka
Hiroyuki
H
Sakamoto
Junichi
J
Kimura
Hiroyuki
H
Nonaka
Masami
M
Kiyota
Yutaka
Y
Momose
Yu
Y
D000818:Animals; D001711:Biotransformation; D001786:Blood Glucose / Q000378:metabolism; D002087:Butyrates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D013055:Spectrophotometry, Infrared; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection; D014280:Triglycerides / Q000097:blood
C488478:(E)-4-(4-((5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy)benzyloxyimino)-4-phenylbutyric acid; D001786:Blood Glucose; D002087:Butyrates; D007004:Hypoglycemic Agents; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides