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 journalArticle

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 languageEnglish
JournalBioorganic and Medicinal Chemistry Letters
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Retinoid X Receptors
Carboxylic Acids
Derivatives
Zebrafish
Transcription
Solubility
Transcriptional Activation
Embryonic Structures
Chemical activation
Ligands
Lipids
imidazo(4,5-b)pyridine

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

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, 01.01.2019.

Research output: Contribution to journalArticle

Takamura, Yuta ; Takahashi, Manami ; Nishii, Midori ; Shibahara, Osamu ; Watanabe, Masaki ; Fujihara, Michiko ; Kakuta, Hiroki. / 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity. In: Bioorganic and Medicinal Chemistry Letters. 2019.
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AU - Watanabe, Masaki

AU - Fujihara, Michiko

AU - Kakuta, Hiroki

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