title: Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Rikimaru
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Abe
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tawaraishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imoto
authors.forename: Jinichi
authors.initials: J
authors.lastname: Yonemori
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirose
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Murase
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsuo
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Chisako
authors.initials: C
authors.lastname: Nomura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsuge
authors.forename: Naoto
authors.initials: N
authors.lastname: Arimura
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Kawakami
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Mol
authors.forename: Gyorgy P
authors.initials: GP
authors.lastname: Snell
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bragstad
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Nozomi
authors.initials: N
authors.lastname: Katayama
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Horiguchi
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
mesh_terms: D000215:Acylation; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D011725:Pyridines; D013449:Sulfonamides