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

Publication date: 15 March 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 6
Author(s): Naoki Teno, Yusuke Iguchi, Yukiko Yamashita, Nobuhiro Mori, Mizuho Une, Tomoko Nishimaki-Mogami, Keigo Gohda
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.

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