Nicotinyl aspartyl ketones as inhibitors of caspase-3

Bioorg Med Chem Lett. 2003 Jul 7;13(13):2137-40. doi: 10.1016/s0960-894x(03)00390-1.

Abstract

Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.

MeSH terms

  • Aldehydes / chemical synthesis
  • Aldehydes / pharmacology
  • Aspartic Acid / chemistry
  • Caspase 3
  • Caspase Inhibitors*
  • Cell Line
  • DNA Fragmentation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Indicators and Reagents
  • Ketones / chemical synthesis*
  • Ketones / pharmacology*
  • Peptide Library
  • Pyridines / chemistry

Substances

  • Aldehydes
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Ketones
  • Peptide Library
  • Pyridines
  • Aspartic Acid
  • CASP3 protein, human
  • Caspase 3