Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: SAR of the N-protecting group

Bioorg Med Chem Lett. 2004 Nov 1;14(21):5295-300. doi: 10.1016/j.bmcl.2004.08.027.

Abstract

This article describes the synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors. The protecting group was found to contribute to caspase-3 inhibiting activity, and compounds with a large group such as Cbz are more active than compounds with a small group such as Ac. Compounds with more hydrophobic protecting groups were found to be more active in cell apoptosis protection assays, probably due to increased cell permeability. MX1122, 2,4-di-Cl-Cbz-Val-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor and is selective for caspases versus other proteases, with good activity in the cell apoptosis protection assays as well as good efficacy in the mouse liver apoptosis model.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Chloromethyl Ketones / chemical synthesis*
  • Amino Acid Chloromethyl Ketones / chemistry
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Caspase 3
  • Caspase Inhibitors*
  • Caspases / metabolism
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • HeLa Cells
  • Humans
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Survival Rate

Substances

  • 2,4-di-Cl-Cbz-Val-Asp-fmk
  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Dipeptides
  • Ketones
  • Protease Inhibitors
  • benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases