A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes.
A novel oxyiminoalkanoic acid derivative, TAK-559, (E)-4-[4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino]-4-phenylbutyric acid, was synthesized as a candidate of a new type of insulin-sensitizing agent. We report here activation of human peroxisome proliferator-activated receptor (hPPAR) subtypes by TAK-559. In a transient transactivation assay, TAK-559 was a potent hPPARgamma1 and hPPARalpha agonist with EC50 values of 31 and 67 nM, respectively. Furthermore, TAK-559 was a partial agonist for hPPARgamma1 with about 68% of maximal activation obtained with rosiglitazone (5-(4-(2-(methyl(2-pyridinyl)amino)ethoxy) benzyl)-1,3-thiazolidine-2,4-dione), a thiazolidinedione derivative, which is known as a PPARgamma agonist. PPARdelta was significantly activated at a high concentration (10 microM) of TAK-559. Competition-binding assays using radiolabeled ligand indicated that the transactivation of all hPPAR subtypes by TAK-559 was due to direct binding of TAK-559 to each subtype. We also demonstrated that TAK-559 acts to recruit the coactivator SRC-1 to each of hPPARgamma1 and hPPARalpha, and to dissociate the corepressor NCoR from each of hPPARgamma1 and hPPARalpha. Taken together, we conclude that TAK-559 is a dual agonist for hPPARgamma1 and hPPARalpha with nearly equal EC50 values, a partial agonist for hPPARgamma1, and has a rather slight agonist activity for hPPARdelta.
Sakamoto
Junichi
J
Pharmaceutical Discovery Center, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Sakamoto_Jyun-ichi@takeda.co.jp
Kimura
Hiroyuki
H
Moriyama
Shinji
S
Imoto
Hiroshi
H
Momose
Yu
Y
Odaka
Hiroyuki
H
Sawada
Hidekazu
H
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051548:Histone Acetyltransferases; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007564:Japan; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
C488478:(E)-4-(4-((5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy)benzyloxyimino)-4-phenylbutyric acid; D002087:Butyrates; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D000077154:Rosiglitazone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1