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.
Kuhn
Bernd
B
F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. bernd.kuhn@roche.com
Hilpert
Hans
H
Benz
Jörg
J
Binggeli
Alfred
A
Grether
Uwe
U
Humm
Roland
R
Märki
Hans Peter
HP
Meyer
Markus
M
Mohr
Peter
P
D015195:Drug Design; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D007211:Indoles; D047493:PPAR alpha; D047495:PPAR gamma; C015292:indolepropionic acid