title: Discovery and optimization of benzimidazole derivatives as a novel chemotype of farnesoid X receptor (FXR) antagonists.
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.
authors.affiliation: 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Teno
authors.affiliation: Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Iguchi
authors.affiliation: Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Hiroshima International University, Faculty of Clinical Nutrition, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Mori
authors.affiliation: Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Une
authors.affiliation: National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.affiliation: Computer-aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Gohda
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001562:Benzimidazoles; D002790:Cholesterol 7-alpha-Hydroxylase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C553219:CYP7A1 protein, human
keywords: Antagonists; Benzimidazole scaffold; Compound library; FXR