Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.
In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists ... with different alpha/gamma EC50 ratios that are selective against the delta-isoform. Analysis of the X-ray complex structure of PPARgamma with the indole propionic acid 13 provides a rationalization for some of the observed SAR.
Mesh Terms:
Drug Design, Indoles, Molecular Structure, PPAR alpha, PPAR gamma, Structure-Activity Relationship, X-Ray Diffraction
Drug Design, Indoles, Molecular Structure, PPAR alpha, PPAR gamma, Structure-Activity Relationship, X-Ray Diffraction
Bioorg Med Chem Lett
Date: Aug. 01, 2006
PubMed ID: 16737814
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