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

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Hamilton GS, Wu YQ, Limburg DC, Wilkinson DE, Vaal MJ, Li JH, Thomas C, Huang W, Sauer H, Ross DT, Soni R, Chen Y, Guo H, Howorth P, Valentine H, Liang S, Spicer D, Fuller M, Steiner JP

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.

PubMed ID

12139466 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Gpi-1046	Peptidyl-prolyl cis-trans isomerase FKBP1A	Ki (nM)	7.5	N/A	N/A	Details