Synthesis and Evaluation of 2-Nonylaminopyridine Derivatives as PPAR Ligands

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 PPARγ 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 PPARγ. Compound 3, with an ethyl group at the C-2 position, was found to be a PPARα/γ dual ligand. Compound 6, the meta isomer of 1, has been shown to be a PPARα ligand. The introduction of methyl (7) and ethyl (8) groups to the C-2 position of the propanoic acid of 6 further improved PPARα-binding potency. In cell-based transactivation assay, compounds 3 and 4 showed dual-agonist activity toward PPARα and PPARγ. Compound 6 was found to be a triple agonist and compound 8 proved to be a selective PPARα 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.