Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists

Mol Divers. 2019 Feb;23(1):19-33. doi: 10.1007/s11030-018-9843-2. Epub 2018 Jul 4.

Abstract

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 μM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 μM) and guggulsterone (IC50 = 45.9 ± 1.1 μM). Docking of A-11 in FXR's ligand-binding domain was also studied.

Keywords: FXR antagonists; Guggulsterone; Molecular docking; SIPI-7623; Structure activity relationship.

MeSH terms

  • Humans
  • Molecular Docking Simulation
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Valerates / chemistry*
  • Valerates / pharmacology*

Substances

  • Receptors, Cytoplasmic and Nuclear
  • Valerates
  • farnesoid X-activated receptor