cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole Based Scaffolds: Design Rationale, Synthesis and Cysteinyl Proteinase Inhibition

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1327-31. doi: 10.1016/j.bmcl.2005.01.022.

Abstract

The 5,5-bicycles cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene 3 and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole 4 were designed as rotationally restricted templates towards the preparation of inhibitors of CAC1 cysteinyl proteinases. The design strategy was exemplified through the solution and solid phase preparation of potent inhibitors of human cathepsin K and may potentially be applied to inhibitors of other CAC1 proteinases.

MeSH terms

  • Cathepsin K
  • Cathepsins / antagonists & inhibitors
  • Cysteine Endopeptidases / drug effects*
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Drug Design
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Molecular Conformation
  • Protein Binding / drug effects
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Pyrazoles
  • Pyrroles
  • cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene
  • cis-6-oxo-hexahydropyrrolo(3,2-c)pyrazole
  • Cathepsins
  • Cysteine Endopeptidases
  • CTSK protein, human
  • Cathepsin K