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

We describe here a novel chemotypewith substituted benzimidazolescaffold 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 antagonismagainst FXR as demonstrated by the derivatives represented by 7 and 15, respectively. Thus, compound 19 arising from the combination of regions A and C underscoredan important fact on antagonismagainst FXR, also showing the reduced small heterodimer partnerand the increased cholesterol 7α-hydroxylase expression levels.