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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 10; pp. 3332 - 3358
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-05-2012; Elsevier
• Subjects: acids; Acylation; Acylsulfonamide; agonists; Animals; benzene; Binding Sites; Biological and medical sciences; Blood Glucose - drug effects; Cercopithecus aethiops; CHO Cells; COS Cells; Cricetinae; Crystallography, X-Ray; Diabetes mellitus; Drug Design; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Isosteric replacement; Male; Medical sciences; Models, Molecular; Peroxisome Proliferator-Activated Receptors - agonists; Pharmacology. Drug treatments; PPARγ agonists; Protein Binding - drug effects; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats, Wistar; SBDD; Structure-Activity Relationship; structure-activity relationships; Sulfonamides - chemistry; Sulfonamides - pharmacology; PPARγ agonists; SBDD; Isosteric replacement; Diabetes mellitus; Acylsulfonamide; Endocrinopathy; Agonist; Nuclear receptor; Sulfonamide; Selectivity; PPAR-γ receptor; Imide; Structure activity relation; Peroxisome proliferator activated receptor; Biological receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.03.036

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.