J Med Chem 2002 Aug 1;45(16):3558-68
Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands.
Wu YQ, Wilkinson DE, Limburg D, Li JH, Sauer H, Ross D, Liang S, Spicer D, Valentine H, Fuller M, Guo H, Howorth P, Soni R, Chen Y, Steiner JP, Hamilton GS.
Department of Research, Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, Maryland 21224.
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.
J Med Chem 2002 Aug 1;45(16):3549-57
Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects.
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.
Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, Maryland 21224.
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.
Bioorg Med Chem Lett 2002 Aug 19;12(16):2189-92
Phosphonate and phosphinate analogues of N-Acylated gamma-glutamylglutamate. potent inhibitors of glutamate carboxypeptidase II.
Tsukamoto T, Flanary JM, Rojas C, Slusher BS, Valiaeva N, Coward JK.
Guilford Pharmaceuticals Inc., 6611 Tributary Street, MD 21224, Baltimore, USA
Phosphonate and phosphinate analogues of N-acylated gamma-glutamylglutamate were tested for the ability to inhibit glutamate carboxypeptidase II (GCP II). All of the compounds inhibit GCP II with IC(50) values in the low nanomolar range. The comparison of the results to previously reported inhibitory studies of the same compounds toward folylpoly-gamma-glutamyl synthetase (FPGS) and gamma-glutamyl hydrolase (gamma-GH) provides insight into structural and mechanistic features of each enzyme. Potential utility of these compounds as diagnostic agents and probes to understand folate or antifolate poly-gamma-glutamates metabolism is also described. |
