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

作者信息

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

机构信息

Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan.

Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan; AIBIOS Co. Ltd., Tri-Seven Roppongi, 8F 7-7-7 Roppongi, Minato-ku, Tokyo 106-0032, Japan.

出版信息

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

DOI:10.1016/j.bmcl.2019.05.050

PMID:31160175

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.

摘要