Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects

J Med Chem. 2002 Aug 1;45(16):3549-57. doi: 10.1021/jm010556c.

Abstract

The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Administration, Oral
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Corpus Striatum / enzymology
  • Corpus Striatum / pathology
  • Corpus Striatum / ultrastructure
  • Dopamine Agents
  • Immunohistochemistry
  • 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
  • Substantia Nigra / enzymology
  • Substantia Nigra / pathology
  • Substantia Nigra / ultrastructure
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Tacrolimus Binding Protein 1A / antagonists & inhibitors*
  • Tacrolimus Binding Protein 1A / chemistry
  • Tyrosine 3-Monooxygenase / metabolism

Substances

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