Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2776-2780. doi: 10.1016/j.bmcl.2017.04.061. Epub 2017 Apr 20.

Abstract

Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC50: 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.

Keywords: PPAR; Rosiglitazone; Transrepression.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Rosiglitazone
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*

Substances

  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone