The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist)

Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branchedalkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl) amino]nicotinic acid(NEt-3 IP: 7a) and6-[ N-ethyl-N-(3-isobutoxy-4- isopropylphenyl)amino]nicotinic acid (NEt-3IB : 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7a) was found to be the first RXRα/β- selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.