3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity

Yuta Takamura; Manami Takahashi; Midori Nishii; Osamu Shibahara; Masaki Watanabe; Michiko Fujihara; Hiroki Kakuta

doi:10.1016/j.bmcl.2019.05.050

3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity

Yuta Takamura, Manami Takahashi, Midori Nishii, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Hiroki Kakuta

Research output: Contribution to journal › Article

Abstract

Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.

Original language	English
Journal	Bioorganic and Medicinal Chemistry Letters
DOIs	https://doi.org/10.1016/j.bmcl.2019.05.050
Publication status	Published - Jan 1 2019

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Keywords

Nuclear receptor
Rexinoid
RXR
Teratogenicity
Zebrafish

ASJC Scopus subject areas

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

Cite this

Takamura, Y., Takahashi, M., Nishii, M., Shibahara, O., Watanabe, M., Fujihara, M., & Kakuta, H. (2019). 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity. Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2019.05.050

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abstract = "Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.",

keywords = "Nuclear receptor, Rexinoid, RXR, Teratogenicity, Zebrafish",

author = "Yuta Takamura and Manami Takahashi and Midori Nishii and Osamu Shibahara and Masaki Watanabe and Michiko Fujihara and Hiroki Kakuta",

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AU - Takamura, Yuta

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AU - Nishii, Midori

AU - Shibahara, Osamu

AU - Watanabe, Masaki

AU - Fujihara, Michiko

AU - Kakuta, Hiroki

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10.1016/j.bmcl.2019.05.050