Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome Proliferator-activated Receptor γ Agonists
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- 作者：Chia-Hui Lin ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：April 23, 2009
- 年：2009
- 卷：52
- 期：8
- 页码：2618-2622
- 全文大小：207K
- 年卷期：v.52,no.8(April 23, 2009)
- ISSN：1520-4804
文摘
Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARα/γ dual agonist 1 to selective PPARγ agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARγ receptor, with 80- to 100-fold PPARγ selectivity over PPARα receptor. X-ray cocrystal studies in PPARγ and modeling studies in PPARα give molecular insights for the improved PPARγ potency and selectivity for 19 when compared to 1.