title: Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists.
abstract: Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Lin
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Peng
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Santhosh Kumar
authors.initials: SK
authors.lastname: Chittimalla
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Liao
authors.forename: Ping-Chiang
authors.initials: PC
authors.lastname: Lyn
authors.forename: Chin-Chieh
authors.initials: CC
authors.lastname: Huang
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Jai-Hong
authors.initials: JH
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Hwei-Jen
authors.initials: HJ
authors.lastname: Lee
authors.forename: Chiun-Gung
authors.initials: CG
authors.lastname: Juo
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D018360:Crystallography, X-Ray; D006885:Hydroxybutyrates / Q000138:chemical synthesis* / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists*; D020033:Protein Isoforms / Q000819:agonists; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry
chemical_list: C540346:2-(1-(3-(4-(biphenyl-4-carbonyl)-2-propylphenoxy)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)-2-methylpropionic acid; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D020033:Protein Isoforms; D011804:Quinolines; D045162:Thiazolidinediones; D000077154:Rosiglitazone