Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
Bioorg Med Chem Lett. 2009 Feb 1;19(3):1001-3. doi: 10.1016/j.bmcl.2008.11.086. Epub 2008 Nov 27.
Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.
视黄醇 X 受体（RXR）配体因其对他莫昔芬耐药性乳腺癌、紫杉醇耐药性肺癌、代谢综合征和过敏的活性而成为临床应用的有吸引力的候选药物。尽管已经报道了几种 RXR 配体，特别是 RXR 拮抗剂，但这些化合物的合理分子设计还没有得到很好的发展。4-[N-甲磺酰基-N-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)氨基]烟酸（5a）是一种中度 RXRalpha 优先激动剂，我们研究了用较长的烷基链或芳环代替磺酰胺上的甲基作为产生新的 RXR 拮抗剂的方法的可行性。得到的几种苯磺酰胺类化合物表现出 RXR 拮抗剂活性。这种设计策略对于解决 RXR 拮抗剂结构多样性不足的问题应该是一种有用的方法。
