2. Academic Validation
  3. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression

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.
Yosuke Toyota 1,  Sayaka Nomura 1,  Makoto Makishima 2,  Yuichi Hashimoto 1,  Minoru Ishikawa 3
Affiliations

Affiliations

  • 1 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
  • 3 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: m-ishikawa@iam.u-tokyo.ac.jp.
PMID: 28465099 DOI: 10.1016/j.bmcl.2017.04.061
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.

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