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 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.
Usui
Shinya
S
Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
Fujieda
Hiroki
H
Suzuki
Takayoshi
T
Yoshida
Naoaki
N
Nakagawa
Hidehiko
H
Ogura
Michitaka
M
Makishima
Makoto
M
Miyata
Naoki
N
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D000631:Aminopyridines; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone