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

Abstract：

: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 β, 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Toyama H,Shirakawa H,Komai M,Hashimoto Y,Fujii S

doi

10.1016/j.bmc.2018.07.038

subject

Has Abstract

pub_date

2018-08-15 00:00:00

pages

4493-4501

issue

15

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(18)30890-3

journal_volume

26

pub_type

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