Development of retinoic acid analog exhibiting a separeted function of the heterodimeric-nuclear receptors

维甲酸X受体（RXR）激动剂是治疗代谢综合征的令人感兴趣的候选物。9-顺式维甲酸（9-Cis-retinoic acid，9 cRA）是一种天然的RXR激动剂，也可作为维甲酸受体（retinoic acid receptor，RAR）激动剂。在RXR激动剂构效关系的研究中，我们合成了9 cRA的环己烯环被大分子疏水基团取代的类似物，并首次合成了具有不同环萜结构的类似物，评价了它们的RXR和RAR激动活性。转录活性测定结果表明，具有薄荷烷骨架的化合物（MentViMe）具有RXR选择性激动活性。接下来，合成作为亲脂性结构域的类似物薄荷酮-苯稠合双环系统（MentPhMe和MentPhEt）。甲基同源物（MentPhMe）显示PPARgamma/RXRa激动活性，另一方面，乙基同源物（MentPhEt）显示LXRalpha/RXRa激动活性。

Retinoid X receptor (RXR) agonists are interesting candidates for the treatment of metabolic syndrome. 9-Cis-retinoic acid (9cRA) is a natural RXR agonist, that also works as a retinoic acid receptor (RAR) agonist. In the study of the structure-activity relationship of RXR agonists, we prepared the analogs, in which the cyclohexene ring of 9cRA is replaced with bulkier hydrophobic moieties.As the first candidates, the analogs having various cyclic terpenoid moieties were synthesized and evaluated their RXR and RAR agonistic activities. The results of transcriptional assay showed that the compound (MentViMe), which possess a menthane skeleton, exhibited RXR-selective agonistic activity. In next, the analogs a menthone-benzene fused bicyclic system as the lipophilic domain (MentPhMe and MentPhEt) were synthesized. The methyl congener (MentPhMe) showed PPARgamma/RXRalpha-agonistic activity, on the other side, the ethyl congener (MentPhEt) showed LXRalpha/RXRalpha-agonistic activity.