Development of novel silanol-based human pregnane X receptor (PXR) agonists with improved receptor selectivity.

Pregnane X receptor (PXR) is a ligand-dependent transcription factor that is considered to be a potential therapeutic target for multiple diseases. Herein, we report the development and structure-activity relationship studies of a new series of hPXR agonists. Focusing on our recently developed silanol-sulfonamide scaffold, we developed the potent hPXR agonist 28, which shows good selectivity over hLXRα and ß, hFXR, and hRORα and γ. Examination of the structure-activity relationship suggested a possible strategy to manipulate the selectivity. Docking simulation indicated the presence of an additional binding cavity and polar contacts in the ligand-binding pocket of hPXR. This information should be helpful for the future development of more potent and selective hPXR ligands.

Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317.

We report the design, synthesis, and physicochemical/biological evaluation of novel silanol derivative 6 (sila-T) as a silanol analog of multi-target nuclear receptor modulator T0901317 (5). Compound 6 showed intermediate hydrophobicity between the corresponding alcohol 13 and perfluoroalcohol 5. While 5 exhibited potent activities toward liver X receptor α and ß, farnesoid X receptor, pregnane X receptor (PXR) and retinoic acid receptor-related orphan receptor (ROR)γ, silanol 6 exhibited activity only toward PXR and RORs. Incorporation of silanol instead of perfluoroalcohol is a promising option for developing novel target-selective, biologically active compounds.

Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure.

Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related orphan receptors (RORs). Therefore, we designed, synthesized and biologically evaluated a series of novel ROR ligands based on the dibenzosilole scaffold as a hydrophobic core structure. Dibenzosilole derivatives bearing a hexafluoro-2-hydroxypropyl group on the benzene ring exhibited significant ROR-inhibitory activity, comparable to that of the lead phenanthridinone derivative 5. Our results indicate that the dibenzosilole skeleton would be a useful scaffold for developing novel biologically active compounds, and that cis-amide structure can be replaced by an alkylsilyl functionality.

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

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 RORß 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, RORß and RORγ was increased compared to that of Am580. The IC50 values for RORα, RORß and RORγ are 1.3, >10 and 4.5 µM, respectively.