Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) 纬 Agonists

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• 作者：Kentaro Rikimaru^a ; ^&dagger ; ; Takeshi Wakabayashi^a ; ^&dagger ; ; Hidenori Abe^a ; ^&dagger ; ; Taisuke Tawaraishi^a ; ^&dagger ; ; Hiroshi Imoto^a ; ^&dagger ; ; Jinichi Yonemori^a ; ^&dagger ; ; Hideki Hirose^a ; ^&dagger ; ; Katsuhito Murase^b ; Takanori Matsuo^a ; ^&Dagger ; ; Mitsuharu Matsumoto^a ; ^&Dagger ; ; Chisako Nomura^a ; ^&Dagger ; ; Hiroko Tsuge^a ; ^&Dagger ; ; Naoto Arimura^a ; ^&Dagger ; ; Kazutoshi Kawakami^a ; ^§ ; ; Junichi Sakamoto^a ; ^§ ; ; Miyuki Funami^a ; ^§ ; ; Clifford D. Mol^c ; Gyorgy P. Snell^c ; Kenneth A. Bragstad^c ; Bi-Ching Sang^c ; Douglas R. Dougan^c ; Toshimasa Tanaka^a ; ^§ ; ; Nozomi Katayama^a ; ^&Dagger ; ; Yoshiaki Horiguchi^a ; ^&dagger ; ; ^鈥?/sup> ; Yu Momose^a ; ^¶ ;
• 关键词：PPAR纬 agonists ; Diabetes mellitus ; SBDD ; Acylsulfonamide ; Isosteric replacement
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 May, 2012
• 卷：20
• 期：10
• 页码：3332-3358
• 文件大小：2910 K

摘要

In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) 纬 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 PPAR纬 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 PPAR纬 ligand-binding domain (LBD). This strategy led to significant improvement of PPAR纬 activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPAR纬 agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPAR纬-LBD revealed the essential structural features of this series of ligands.