3H-Imidazo[4, 5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity. Issue 15 (1st August 2019)

• Record Type: Journal Article
• Authors: Takamura, Yuta; Takahashi, Manami; Nishii, Midori; Shibahara, Osamu; Watanabe, Masaki; Fujihara, Michiko; Kakuta, Hiroki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 15(2019)
• Page Start: 1891
• Page End: 1894
• Publication Date: 2019-08-01
• Subjects: CTCL cutaneous T cell lymphoma -- EC50 half-maximal effective concentration -- Emax efficacy maximal response -- PPAR peroxisome proliferator-activated receptor -- RAR retinoic acid receptor -- RXR retinoid X receptor -- TPT triphenyltin; Nuclear receptor -- RXR -- Rexinoid -- Teratogenicity -- Zebrafish; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.05.050
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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)-3 H -imidazo[4, 5- b ]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.