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Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists.

Abstract：

:Activation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells. With this activity and a favorable toxicity-, stability- and selectivity-profile it appears suitable to further study FXR antagonism in vitro and in vivo.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Schmidt J,Schierle S,Gellrich L,Kaiser A,Merk D

doi

10.1016/j.bmc.2018.07.017

subject

Has Abstract

pub_date

2018-08-07 00:00:00

pages

4240-4253

issue

14

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(18)31006-X

journal_volume

26

pub_type

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