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

Bioorg Med Chem Lett. 2019 Aug 1;29(15):1891-1894. doi: 10.1016/j.bmcl.2019.05.050. Epub 2019 May 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Acids / adverse effects*
  • Humans
  • Retinoid X Receptors / adverse effects*
  • Teratogenesis / drug effects*
  • Zebrafish

Substances

  • Carboxylic Acids
  • Retinoid X Receptors