title: Replacement of the hydrophobic part of 9-cis-retinoic acid with cyclic terpenoid moiety results in RXR-selective agonistic activity.
abstract: Retinoid X receptor (RXR) agonists are interesting candidates for the treatment of metabolic syndrome. 9-Cis-retinoic acid (9cRA: 1) is a natural RXR agonist, that also works as a retinoic acid receptor (RAR) agonist. This fact prompted us to study the structure-activity relationship (SAR) of RXR agonists derived from 1. Though 3 and 4, in which the cyclohexene part of 1 is replaced with bulkier hydrophobic moieties, show RXR-selective agonistic activity, some analogs containing other ring structures show RAR agonistic activity. Thus, we were interested in establishing what kind of ring skeleton is required for RXR-selective agonistic activity. In this study, we systematically prepared 5 and 6, in which the cyclohexene ring of 1 is replaced with various cyclic terpenoid moieties, and evaluated their RXR and RAR agonistic activities. Our previously reported CsF-promoted Stille coupling reaction was employed as a key step for the comprehensive synthesis of 5 and 6. The results of transcriptional assay showed that compounds 5b-f, which possess a menthane skeleton, exhibit RXR-selective agonistic activity. These results should be helpful for the design of superior RXR-selective agonists based on the structure of 1.
authors.affiliation: Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okitsu
authors.forename: Kana
authors.initials: K
authors.lastname: Sato
authors.forename: Kinya
authors.initials: K
authors.lastname: Iwatsuka
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sawada
authors.forename: Kimie
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Okano
authors.forename: Shoya
authors.initials: S
authors.lastname: Yamada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.forename: Akimori
authors.initials: A
authors.lastname: Wada
mesh_terms: D000077556:Alitretinoin; D001665:Binding Sites; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry*; D014212:Tretinoin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047488:Retinoid X Receptors; D013729:Terpenes; D000077556:Alitretinoin; D014212:Tretinoin