Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists

  • J Med Chem. 2009 Apr 23;52(8):2618-22. doi: 10.1021/jm801594x.
Chia-Hui Lin  1 ,  Yi-Hui Peng ,  Mohane Selvaraj Coumar ,  Santhosh Kumar Chittimalla ,  Chun-Chen Liao ,  Ping-Chiang Lyn ,  Chin-Chieh Huang ,  Tzu-Wen Lien ,  Wen-Hsing Lin ,  John T-A Hsu ,  Jai-Hong Cheng ,  Xin Chen ,  Jian-Sung Wu ,  Yu-Sheng Chao ,  Hwei-Jen Lee ,  Chiun-Gung Juo ,  Su-Ying Wu ,  Hsing-Pang Hsieh
Affiliations
  • 1. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
PMID: 19301897 DOI: 10.1021/jm801594x
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.

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