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Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.

Bioorganic & medicinal chemistry letters (2006-06-02)
Bernd Kuhn, Hans Hilpert, Jörg Benz, Alfred Binggeli, Uwe Grether, Roland Humm, Hans Peter Märki, Markus Meyer, Peter Mohr
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3-Indolepropionic acid, ReagentPlus®, 99%
Sigma-Aldrich
Indole-3-propionic acid, ≥99.0% (T)
Sigma-Aldrich
Indole-3-propionic acid, ≥97.0% (T)