Discovery and optimization of benzimidazole derivatives as a novel chemotype of farnesoid X receptor (FXR) antagonists.

Authors :: Teno N
Iguchi Y
Yamashita Y
Mori N
Une M
Nishimaki-Mogami T
Gohda K
Source :: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Mar 15; Vol. 25 (6), pp. 1787-1794. Date of Electronic Publication: 2017 Jan 31.
Publication Year :: 2017
Abstract: We describe here a novel chemotype with substituted benzimidazole scaffold for nonsteroidal farnesoid X receptor (FXR) antagonists starting from the identification of a screening hit, BB-4. Structure diversity in four regions A-D of BB-4 or 1 is discussed. In particular, regions A and C had an effect on an antagonism against FXR as demonstrated by the derivatives represented by 7 and 15, respectively. Thus, compound 19 arising from the combination of regions A and C underscored an important fact on antagonism against FXR, also showing the reduced small heterodimer partner and the increased cholesterol 7α-hydroxylase expression levels.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Subjects :: Benzimidazoles chemistry
Cell Line, Tumor
Cholesterol 7-alpha-Hydroxylase genetics
Cholesterol 7-alpha-Hydroxylase metabolism
Fluorescence Resonance Energy Transfer
Humans
Proton Magnetic Resonance Spectroscopy
RNA, Messenger genetics
Structure-Activity Relationship
Benzimidazoles pharmacology
Drug Discovery
Receptors, Cytoplasmic and Nuclear antagonists & inhibitors

Full Text Access

Tools