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 › peer-review

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
Externally published	Yes

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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3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity. / Takamura, Yuta; Takahashi, Manami; Nishii, Midori; Shibahara, Osamu; Watanabe, Masaki; Fujihara, Michiko; Kakuta, Hiroki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 15, 01.08.2019, p. 1891-1894.

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

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

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, RXR, Rexinoid, Teratogenicity, Zebrafish",

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

year = "2019",

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doi = "10.1016/j.bmcl.2019.05.050",

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AU - Takamura, Yuta

AU - Takahashi, Manami

AU - Nishii, Midori

AU - Shibahara, Osamu

AU - Watanabe, Masaki

AU - Fujihara, Michiko

AU - Kakuta, Hiroki

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N2 - 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.

AB - 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.

KW - Nuclear receptor

KW - RXR

KW - Rexinoid

KW - Teratogenicity

KW - Zebrafish

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JO - Bioorganic and Medicinal Chemistry Letters

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

Abstract

Keywords

ASJC Scopus subject areas

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