Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4233-6. doi: 10.1016/j.bmcl.2006.05.076. Epub 2006 Jun 16.

Abstract

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / chemical synthesis*
  • Caspase 8
  • Caspase Inhibitors*
  • Chemistry, Pharmaceutical / methods
  • Cysteine Endopeptidases / metabolism
  • Drug Industry / methods
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrazines / chemical synthesis*
  • Hydrazines / pharmacology*
  • Inhibitory Concentration 50
  • Models, Chemical

Substances

  • Amides
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Hydrazines
  • Aminoimidazole Carboxamide
  • CASP8 protein, human
  • Caspase 8
  • Cysteine Endopeptidases