title: Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors.
abstract: Retinoic acid receptor (RAR)-related orphan receptors (RORs) regulate a variety of physiological processes, including hepatic gluconeogenesis, lipid metabolism, circadian rhythm and immune function. The RAR agonist: all-trans retinoic acid was reported to be an RORβ inverse agonist, but no information is available regarding ROR activity of its synthetic analogue Am580. Therefore, we screened Am580 and some related tetramethyltetrahydronaphthalene derivatives and carried out structural development studies, including substitution of carbon atoms with silicon, with the aim of creating a potent ROR transcriptional inhibitor. The phenyl amide disila compound 22 showed the most potent ROR-inhibitory activity among the compounds examined. Its activity towards RORα, RORβ and RORγ was increased compared to that of Am580. The IC₅₀ values for RORα, RORβ and RORγ are 1.3, >10 and 4.5 μM, respectively.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: hashimot@iam.u-tokyo.ac.jp.
authors.forename: Hirozumi
authors.initials: H
authors.lastname: Toyama
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Nakagomi
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000819:agonists*; D017646:Organosilicon Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012825:Silicon / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000593081:1,1,4,4-tetramethyl-N-phenyl-1,2,3,4-tetrahydrobenzo-1,4-disiline-6-carboxamide; D000813:Anilides; D001565:Benzoates; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D017646:Organosilicon Compounds; C539738:RORA protein, human; D013764:Tetrahydronaphthalenes; C068073:Am 580; D012825:Silicon
keywords: Inverse agonist; Retinoic acid receptor-related orphan receptor; Silicon