Design and synthesis of a potent and selective peptidomimetic inhibitor of caspase-3

J Med Chem. 2004 Dec 16;47(26):6455-8. doi: 10.1021/jm049248f.

Abstract

In this paper we report the synthesis and characterization of a novel potent and selective inhibitor of caspase-3, a member of the caspase family of cysteine proteases which plays an important role in many human disorders. This molecule represents 3(S)-acetylamino-N-[1-[(((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)methyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]succinamic acid, a monocyclic conformationally constrained form of the tetrapeptide Ac-DEVD-H, in which a 1,4-benzodiazepine nucleus is introduced internally to the peptidic sequence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemical synthesis*
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / pharmacology
  • Benzodiazepinones / chemical synthesis*
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology
  • Caspase 3
  • Caspase Inhibitors*
  • Caspases / chemistry
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Humans
  • Molecular Conformation
  • Oligopeptides / chemistry*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 3-acetylamino-N-(1-(((2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)methyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)succinamic acid
  • Benzodiazepinones
  • Caspase Inhibitors
  • Oligopeptides
  • Recombinant Proteins
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • 4-Butyrolactone