A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes

Abstract 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 hPPARγ1 and hPPARα agonist with EC 50 values of 31 and 67 nM, respectively. Furthermore, TAK-559 was a partial agonist for hPPARγ1 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 PPARγ agonist. PPARδ was significantly activated at a high concentration (10 μM) 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 hPPARγ1 and hPPARα, and to dissociate the corepressor NCoR from each of hPPARγ1 and hPPARα. Taken together, we conclude that TAK-559 is a dual agonist for hPPARγ1 and hPPARα with nearly equal EC 50 values, a partial agonist for hPPARγ1, and has a rather slight agonist activity for hPPARδ.