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

Gregory S. Hamilton, Yong Qian Wu, David C. Limburg, Douglas E. Wilkinson, Mark J. Vaal, Jia He Li, Christine Thomas, Wei Huang, Hansjorg Sauer, Douglas T. Ross, Raj Soni, Yi Chen, Hongshi Guo, Pamela Howorth, Heather Valentine, Shi Liang, Dawn Spicer, Mike Fuller, Joseph P. Steiner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3549-3557
Number of pages9
JournalJournal of medicinal chemistry
Volume45
Issue number16
DOIs
StatePublished - Aug 1 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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