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Identification of potent farnesoid X receptor (FXR) antagonist showing favorable PK profile and distribution toward target tissues: Comprehensive understanding of structure-activity relationship of FXR antagonists.

Abstract：

:Antagonizing transcriptional activity of farnesoid X receptor (FXR) in the intestine has been reported as an effective means for the treatment of nonalcoholic fatty liver disease, type 2 diabetes and obesity. We describe herein that the building blocks necessary to maintain the antagonism of our chemotype were investigated in order to modulate in vivo pharmacokinetic behavior and the tissue distribution without blunting the activity against FXR. A comprehensive understanding of the structure-activity relationship led to analog 30, which is superior to 12 in terms of its pharmacokinetic profiles by oral administration and its tissue distribution toward target tissues (liver and ileum) in rats while preserving the in vitro activity of 12 against FXR. Thus, 30 should be a candidate compound to investigate the effects of inhibiting FXR activity while simultaneously improving the outcome of nonalcoholic fatty liver disease, type 2 diabetes and obesity.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Teno N,Yamashita Y,Masuda A,Iguchi Y,Oda K,Fujimori K,Hiramoto T,Nishimaki-Mogami T,Une M,Gohda K

doi

10.1016/j.bmc.2019.04.029

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

2220-2227

issue

11

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)30375-X

journal_volume

27

pub_type

杂志文章

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