Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB

Mariko Nakayama; Shoya Yamada; Fuminori Ohsawa; Yui Ohta; Kohei Kawata; Makoto Makishima; Hiroki Kakuta

doi:10.1021/ml200197e

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB

ACS Med Chem Lett. 2011 Sep 27;2(12):896-900. doi: 10.1021/ml200197e. eCollection 2011 Dec 8.

Authors

Mariko Nakayama¹, Shoya Yamada¹, Fuminori Ohsawa¹, Yui Ohta¹, Kohei Kawata¹, Makoto Makishima², Hiroki Kakuta¹

Affiliations

¹ Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
² Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Abstract

We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).

Keywords: RXR; Synthetic route; agonists; antagonists; nuclear receptors; retinoids.