Development of improved PPARβ/δ inhibitors.
GSK0660 (1) is the first peroxisome proliferator-activated receptor (PPAR) β/δ-selective inhibitory ligand described in the literature. Based on its structure, we designed and synthesized a series of modified compounds to establish preliminary structure-activity relationships. Most beneficial for increased binding affinity towards the PPARβ/δ ligand binding domain was the replacement of the 4'-aminophenyl substituent by medium-length n-alkyl chains, such as n-butyl or iso-pentyl. These compounds show activity down to the one-digit nanomolar range, thus possessing up to a tenfold higher binding affinity compared with GSK0660. Additionally, the subtype-specific inhibition of PPARβ/δ was confirmed in a cell-based assay making these compounds invaluable tools for the further exploration of the functions of PPARβ/δ.
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marburg, Germany.
Philipp M
PM
Toth
Simone
S
Naruhn
Veronika F S
VF
Pape
Stefanie M A
SM
Dörr
Gerhard
G
Klebe
Rolf
R
Müller
Wibke E
WE
Diederich
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D047494:PPAR delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048068:PPAR-beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C529769:GSK0660; D047494:PPAR delta; D048068:PPAR-beta; D013450:Sulfones; D013876:Thiophenes