Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors

Hirozumi Toyama; Masaharu Nakamura; Masahiko Nakamura; Yotaro Matsumoto; Madoka Nakagomi; Yuichi Hashimoto

doi:10.1016/j.bmc.2014.01.023

Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors

Bioorg Med Chem. 2014 Mar 15;22(6):1948-59. doi: 10.1016/j.bmc.2014.01.023. Epub 2014 Feb 8.

Authors

Hirozumi Toyama¹, Masaharu Nakamura², Masahiko Nakamura², Yotaro Matsumoto³, Madoka Nakagomi⁴, Yuichi Hashimoto²

Affiliations

¹ 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.
² Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
³ Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
⁴ Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.

PMID: 24559867
DOI: 10.1016/j.bmc.2014.01.023

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.

Keywords: Inverse agonist; Retinoic acid receptor-related orphan receptor; Silicon.

MeSH terms

Anilides / chemical synthesis
Anilides / chemistry
Anilides / pharmacology*
Benzoates / chemical synthesis
Benzoates / chemistry
Benzoates / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Nuclear Receptor Subfamily 1, Group F, Member 1 / agonists*
Organosilicon Compounds / chemical synthesis
Organosilicon Compounds / chemistry
Organosilicon Compounds / pharmacology*
Silicon / chemistry*
Structure-Activity Relationship
Tetrahydronaphthalenes / chemical synthesis
Tetrahydronaphthalenes / chemistry
Tetrahydronaphthalenes / pharmacology*

Substances

1,1,4,4-tetramethyl-N-phenyl-1,2,3,4-tetrahydrobenzo-1,4-disiline-6-carboxamide
Anilides
Benzoates
Nuclear Receptor Subfamily 1, Group F, Member 1
Organosilicon Compounds
RORA protein, human
Tetrahydronaphthalenes
Am 580
Silicon