Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists

Bioorg Med Chem. 2012 Jun 1;20(11):3429-45. doi: 10.1016/j.bmc.2012.04.021. Epub 2012 Apr 20.

Abstract

A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20 μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Gene Expression Profiling
  • Hep G2 Cells
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Structure-Activity Relationship*
  • Thiazepines / chemical synthesis*
  • Thiazepines / pharmacology*
  • User-Computer Interface

Substances

  • Pyrazoles
  • Receptors, Cytoplasmic and Nuclear
  • Thiazepines
  • farnesoid X-activated receptor
  • pyrazole
  • Luciferases