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
Pages (from-to)	1891-1894
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2019.05.050
Publication status	Published - Aug 1 2019

Keywords

Nuclear receptor
RXR
Rexinoid
Teratogenicity
Zebrafish

ASJC Scopus subject areas

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

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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, 29(15), 1891-1894. https://doi.org/10.1016/j.bmcl.2019.05.050

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AU - Shibahara, Osamu

AU - Watanabe, Masaki

AU - Fujihara, Michiko

AU - Kakuta, Hiroki

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