Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4411(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yI)-4-hydroxyphenyl)acrylic Acid (CD3254)
Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4411(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yI)-4-hydroxyphenyl)acrylic Acid (CD3254)
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DOI：
10.1021/jm4008517
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发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Wagner, Carl E.
中科院分区：
文献类型：
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作者：
Jurutka, Peter W.;Kaneko, Ichiro;Wagner, Carl E.
44143,5,5,8,8pentamethyl-5-6-7-8-tetrahydro-2-naphthypethynyll苯甲酸 (1) 的三种未报道的类似物，也称为贝沙罗汀，以及 描述并评估了 (E)-3-(3-(1,2,3,4-四氢-1,1,4,4,6-五甲基萘-7-y1)-4-羟基苯基)丙烯酸 (CD3254) 的类视黄醇 X 受体 (RXR) 选择性激动作用。化合物 1 已获得 FDA 批准用于治疗皮肤 T 细胞淋巴瘤 (CTCL)，但使用 1 进行治疗可能会因破坏其他 RXR 异二聚体受体途径而引起副作用。在七种模拟的新化合物中，所有类似物在哺乳动物 2 杂交和 RXRE 介导的测定中刺激 RXR 调节的转录，根据 EC50 图谱具有相当或更高的生物活性，并且与 1 相比，在 CTCL 测定中保留相似或改进的细胞凋亡活性。与 1 相比，所有新化合物都表现出对 RXR 的选择性和与视黄酸受体 (RAR) 的最小交叉。 全反式视黄酸，其精选类似物还可减少对其他 RXR 依赖性途径（例如 VDR-RXR）的抑制。我们的结果表明，通过合理的药物设计可以进一步提高贝沙罗汀的生物效力和选择性。
Three unreported analogues of 44143,5,5,8,8pentamethyl-5-6-7-8-tetrahydro-2-naphthypethynyllbenzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-y1)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.