Bioorganic and Medicinal Chemistry p. 3332 - 3358 (2012)
Update date:2022-08-05
Topics:
Rikimaru, Kentaro
Wakabayashi, Takeshi
Abe, Hidenori
Tawaraishi, Taisuke
Imoto, Hiroshi
Yonemori, Jinichi
Hirose, Hideki
Murase, Katsuhito
Matsuo, Takanori
Matsumoto, Mitsuharu
Nomura, Chisako
Tsuge, Hiroko
Arimura, Naoto
Kawakami, Kazutoshi
Sakamoto, Junichi
Funami, Miyuki
Mol, Clifford D.
Snell, Gyorgy P.
Bragstad, Kenneth A.
Sang, Bi-Ching
Dougan, Douglas R.
Tanaka, Toshimasa
Katayama, Nozomi
Horiguchi, Yoshiaki
Momose, Yu
In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.
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