Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists.
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.
Lin
Chia-Hui
CH
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Peng
Yi-Hui
YH
Coumar
Mohane Selvaraj
MS
Chittimalla
Santhosh Kumar
SK
Liao
Chun-Chen
CC
Lyn
Ping-Chiang
PC
Huang
Chin-Chieh
CC
Lien
Tzu-Wen
TW
Lin
Wen-Hsing
WH
Hsu
John T-A
JT
Cheng
Jai-Hong
JH
Chen
Xin
X
Wu
Jian-Sung
JS
Chao
Yu-Sheng
YS
Lee
Hwei-Jen
HJ
Juo
Chiun-Gung
CG
Wu
Su-Ying
SY
Hsieh
Hsing-Pang
HP
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
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