title: Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.
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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. bernd.kuhn@roche.com
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Hans
authors.initials: H
authors.lastname: Hilpert
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Alfred
authors.initials: A
authors.lastname: Binggeli
authors.forename: Uwe
authors.initials: U
authors.lastname: Grether
authors.forename: Roland
authors.initials: R
authors.lastname: Humm
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Märki
authors.forename: Markus
authors.initials: M
authors.lastname: Meyer
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
mesh_terms: 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
chemical_list: D007211:Indoles; D047493:PPAR alpha; D047495:PPAR gamma; C015292:indolepropionic acid