Structure-activity relationship study of a series of caspase inhibitors containing γ-amino acid moiety for treatment of cholestatic liver disease

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1874-1878. doi: 10.1016/j.bmcl.2018.04.002. Epub 2018 Apr 4.

Abstract

A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.

Keywords: Apoptosis; Caspase inhibitor; Chronic liver disease; γ-Amino acid.

MeSH terms

  • Amino Acids / chemistry*
  • Animals
  • Bilirubin / blood
  • Binding Sites
  • Caspase 1 / chemistry
  • Caspase 1 / metabolism
  • Caspase Inhibitors / chemistry*
  • Caspase Inhibitors / pharmacokinetics
  • Caspase Inhibitors / therapeutic use
  • Disease Models, Animal
  • Half-Life
  • Humans
  • Jurkat Cells
  • Liver Diseases / drug therapy
  • Liver Diseases / pathology
  • Mice
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • fas Receptor / antagonists & inhibitors
  • fas Receptor / metabolism

Substances

  • Amino Acids
  • Caspase Inhibitors
  • FAS protein, human
  • fas Receptor
  • Caspase 1
  • Bilirubin