To find novel
PPAR ligands, we prepared several 3-{3 or 4-[2-(nonylpyridin-2-ylamino)
ethoxy]
phenyl}
propanoic acid derivatives which were designed based on the structure of our previous PPARgamma ligand 1. In
PPAR binding affinity
assays, compound 4, which had an
ethoxy group at the C-2 position of the
propanoic acid of 1, showed
selective binding affinity for PPARgamma. Compound 3, with an
ethyl group at the C-2 position, was found to be a PPARalpha/gamma dual ligand. Compound 6, the
meta isomer of 1, has been shown to be a PPARalpha ligand. The introduction of
methyl (7) and ethyl (8) groups to the C-2 position of the
propanoic acid of 6 further improved PPARalpha-binding potency. In cell-based transactivation
assay, compounds 3 and 4 showed dual-agonist activity toward PPARalpha and PPARgamma. Compound 6 was found to be a triple
agonist and compound 8 proved to be a
selective PPARalpha
agonist. In the human hypodermic
preadipocyte differentiation test, it was demonstrated that the maximal activity of compounds 3 and 4 was higher than that of
rosiglitazone.
