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

Yosuke Toyota; Sayaka Nomura; Makoto Makishima; Yuichi Hashimoto; Minoru Ishikawa

doi:10.1016/j.bmcl.2017.04.061

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

Yosuke Toyota, Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

LIF - Molecular and Chemical Life Science

Research output: Contribution to journal › Article

3 Citations (Scopus)

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: 14 μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.

Original language	English
Pages (from-to)	2776-2780
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2017.04.061
Publication status	Published - 2017

Keywords

PPAR
Rosiglitazone
Transrepression

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Toyota, Y., Nomura, S., Makishima, M., Hashimoto, Y., & Ishikawa, M. (2017). Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression. Bioorganic and Medicinal Chemistry Letters, 27(12), 2776-2780. https://doi.org/10.1016/j.bmcl.2017.04.061

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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: 14 μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.",

keywords = "PPAR, Rosiglitazone, Transrepression",

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AU - Ishikawa, Minoru

PY - 2017

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AB - 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: 14 μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.

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