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

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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.