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

Naoki Teno; Yusuke Iguchi; Yukiko Yamashita; Nobuhiro Mori; Mizuho Une; Tomoko Nishimaki-Mogami; Keigo Gohda

doi:10.1016/j.bmc.2017.01.040

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

Bioorg Med Chem. 2017 Mar 15;25(6):1787-1794. doi: 10.1016/j.bmc.2017.01.040. Epub 2017 Jan 31.

Authors

Naoki Teno¹, Yusuke Iguchi², Yukiko Yamashita², Nobuhiro Mori³, Mizuho Une², Tomoko Nishimaki-Mogami⁴, Keigo Gohda⁵

Affiliations

¹ Hiroshima International University, Faculty of Clinical Nutrition, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan. Electronic address: n-teno@ps.hirokoku-u.ac.jp.
² Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
³ Hiroshima International University, Faculty of Clinical Nutrition, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
⁴ National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
⁵ Computer-aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, Japan.

PMID: 28190654
DOI: 10.1016/j.bmc.2017.01.040

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.

Keywords: Antagonists; Benzimidazole scaffold; Compound library; FXR.

MeSH terms

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

Substances

Benzimidazoles
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
farnesoid X-activated receptor
CYP7A1 protein, human
Cholesterol 7-alpha-Hydroxylase