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Development of Improved PPAR β / δ Inhibitors
Author(s) -
Toth Philipp M.,
Naruhn Simone,
Pape Veronika F. S.,
Dörr Stefanie M. A.,
Klebe Gerhard,
Müller Rolf,
Diederich Wibke E.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100408
Subject(s) - substituent , ligand (biochemistry) , peroxisome proliferator activated receptor , chemistry , stereochemistry , receptor , alkyl , structure–activity relationship , competitive binding , combinatorial chemistry , peroxisome , binding site , in vitro , biochemistry , organic chemistry
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 PPAR β / 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 PPAR β / δ was confirmed in a cell‐based assay making these compounds invaluable tools for the further exploration of the functions of PPAR β / δ .