Development of Improved PPARβ/δ Inhibitors

• Published in: ChemMedChem 2012-01, Vol.7 (1), p.159-170
• Main Authors: Toth, Philipp M., Naruhn, Simone, Pape, Veronika F. S., Dörr, Stefanie M. A., Klebe, Gerhard, Müller, Rolf, Diederich, Wibke E.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; GSK0660; Humans; inhibitors; NR1C2; nuclear receptors; PPAR delta - antagonists & inhibitors; PPAR delta - metabolism; PPAR-beta - antagonists & inhibitors; PPAR-beta - metabolism; PPARβ/δ; Structure-Activity Relationship; structure-activity relationships; Sulfones - chemistry; Sulfones - pharmacology; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100408

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. Ten‐times better! Structural optimization of the PPARβ/δ‐selective inhibitor GSK0660 (1) revealed that replacement of the 4′‐aminophenyl substituent by medium‐length n‐alkyl chains is most beneficial for an increased binding affinity. The compounds presented here show activity down to the one‐digit nanomolar range representing up to a tenfold higher binding affinity compared with 1.