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

Peng Liu; Xing Xu; Lili Chen; Lei Ma; Xu Shen; Lihong Hu

doi:10.1016/j.bmc.2014.01.032

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

Bioorg Med Chem. 2014 Mar 1;22(5):1596-607. doi: 10.1016/j.bmc.2014.01.032. Epub 2014 Jan 30.

Authors

Peng Liu¹, Xing Xu², Lili Chen², Lei Ma¹, Xu Shen³, Lihong Hu⁴

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
² Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: lhhu@simm.ac.cn.
⁴ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: xshen@mail.shcnc.ac.cn.

PMID: 24513188
DOI: 10.1016/j.bmc.2014.01.032

Abstract

Compound 1 (IC50=35.2 ± 7.2 μM), 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 ± 0.1μM. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity.

Keywords: FXR antagonist; Hydroxyacetophenone derivatives; Non-steroidal; SAR study.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetophenones / chemistry*
Humans
Receptor, Farnesoid X-Activated
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
Receptors, Cytoplasmic and Nuclear / chemistry
Structure-Activity Relationship

Substances

Acetophenones
Receptors, Cytoplasmic and Nuclear
Receptor, Farnesoid X-Activated
4-hydroxyacetophenone