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

Research output: Contribution to journal › Article › peer-review

5 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
Externally published	Yes

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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title = "Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression",

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",

author = "Yosuke Toyota and Sayaka Nomura and Makoto Makishima and Yuichi Hashimoto and Minoru Ishikawa",

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year = "2017",

doi = "10.1016/j.bmcl.2017.04.061",

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AU - Toyota, Yosuke

AU - Nomura, Sayaka

AU - Makishima, Makoto

AU - Hashimoto, Yuichi

AU - Ishikawa, Minoru

PY - 2017

Y1 - 2017

N2 - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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