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

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Lin CH, Peng YH, Coumar MS, Chittimalla SK, Liao CC, Lyn PC, Huang CC, Lien TW, Lin WH, Hsu JT, Cheng JH, Chen X, Wu JS, Chao YS, Lee HJ, Juo CG, Wu SY, Hsieh HP

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.

PubMed ID

19301897 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor alpha	EC 50 (nM)	>10000	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor delta	EC 50 (nM)	>10000	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	220	N/A	N/A	Details