Discovery and SAR study of hydroxyacetophenone derivatives as potent, non-steroidal farnesoid X receptor (FXR) antagonists

Compound 1 (IC50 = 35.2 +/- 7.2 mu M), a moderate FXR antagonist was discovered via high-throughput screening. Structure-activity relationship studies indicated that the shape and the lipophilicity of the substituents of the aromatic ring affect the activity dramatically, increasing the shape and the lipophilicity of the substituents of the aromatic ring enhances the potency of FXR antagonists. Especially, when the OH at C2 position of the aromatic ring was replaced by the OBn substituent (analog 2b), its activity could be improved to IC50 = 1.1 +/- 0.1 mu M. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity. (C) 2014 Elsevier Ltd. All rights reserved.