Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands

J Med Chem. 2002 Aug 1;45(16):3558-68. doi: 10.1021/jm0200456.

Abstract

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Dopamine Agents
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology
  • Ligands
  • Mice
  • Molecular Mimicry
  • Nerve Regeneration / drug effects
  • Neurites / drug effects
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy
  • Parkinson Disease, Secondary / pathology
  • Pipecolic Acids / chemical synthesis*
  • Pipecolic Acids / chemistry
  • Pipecolic Acids / pharmacology
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis*
  • Proline / chemistry
  • Proline / pharmacology
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Tacrolimus Binding Protein 1A / antagonists & inhibitors*
  • Tacrolimus Binding Protein 1A / chemistry

Substances

  • Dopamine Agents
  • Ketones
  • Ligands
  • Neuroprotective Agents
  • Pipecolic Acids
  • Sulfhydryl Compounds
  • Proline
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tacrolimus Binding Protein 1A