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有趣候选药物。9-顺式维甲酸(9cRA)是一种天然的RXR激动剂，也是一种维甲酸受体(RAR)激动剂。在RXR激动剂的构效关系研究中，我们制备了用更大的疏水基团取代9cRA的环己烯环的类似物，作为第一个候选化合物，合成了具有不同环萜类基团的类似物，并对其RXR和RAR激动剂的活性进行了评价。转录实验结果表明，具有薄荷烷骨架的化合物(MentViMe)具有RXR选择性激动剂活性。接下来，合成了作为亲脂结构域的类似物薄荷酮-苯双环体系(MentPhMe和MentPhEt)。甲基异构体(MentPhMe)表现出PPARGamma/RXRα激动剂活性，而乙基异构体(MentPhEt)表现出LXRα/RXRα激动剂活性。

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.