Discovery and SAR study of 3-(tert-butyl)-4-hydroxyphenyl benzoate and benzamide derivatives as novel farnesoid X receptor (FXR) antagonists

Bioorg Med Chem. 2015 Oct 1;23(19):6427-36. doi: 10.1016/j.bmc.2015.08.021. Epub 2015 Aug 20.

Abstract

3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) was discovered in our in-house high throughput screening as a moderate FXR antagonist. To improve the potency and the stability of the hit 1, forty derivatives were synthesized and SAR was systematically explored. The results turn out that replacing the 2,4-dichlorophenyl with 2,6-dichloro-4-amidophenyl shows great improvement in potency, replacing the benzoate with benzamide shows improvement in stability and slight declining of potency and 3-(tert-butyl)-4-hydroxyphenyl unit is essential in obtaining the FXR antagonistic activity.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzoates / chemistry*
  • Benzoates / metabolism
  • Drug Evaluation, Preclinical
  • Humans
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Benzoates
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • benzamide