Structure-based design of indole propionic acids as novel PPARα/γ co-agonists
Bernd Kuhna b✉, Hans Hilpertb✉, Jörg Benzb, Alfred Binggelib, Uwe Gretherb, Roland Hummb, Hans Peter Märkib, Markus Meyerb, Peter Mohrb
- aF. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. bernd.kuhn@roche.com
- bF. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland
- ✉Corresponding author
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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.
TL;DRAnalysis of the X-ray complex structure of PPARγ with the indole propionic acid 13 provides a rationalization for some of the observed SAR. (Semantic Scholar)