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Your search keyword '"Pipecolic Acids chemical synthesis"' showing total 4 results
Start Over Descriptor "Pipecolic Acids chemical synthesis" Topic tacrolimus binding protein 1a
4 results on '"Pipecolic Acids chemical synthesis"'

1. Synthesis, molecular modeling and biological evaluation of aza-proline and aza-pipecolic derivatives as FKBP12 ligands and their in vivo neuroprotective effects.

Author

Wilkinson DE, Thomas BE 4th, Limburg DC, Holmes A, Sauer H, Ross DT, Soni R, Chen Y, Guo H, Howorth P, Valentine H, Spicer D, Fuller M, Steiner JP, Hamilton GS, and Wu YQ

Subjects
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine antagonists & inhibitors, Animals, Aza Compounds chemical synthesis, Aza Compounds chemistry, Aza Compounds pharmacology, Corpus Striatum drug effects, Corpus Striatum metabolism, Dose-Response Relationship, Drug, Ligands, Male, Mice, Mice, Inbred Strains, Models, Molecular, Neuroprotective Agents chemistry, Pipecolic Acids chemistry, Proline chemical synthesis, Proline chemistry, Proline pharmacology, Structure-Activity Relationship, Tacrolimus Binding Protein 1A chemistry, Tyrosine 3-Monooxygenase metabolism, Neuroprotective Agents chemical synthesis, Neuroprotective Agents pharmacology, Pipecolic Acids chemical synthesis, Pipecolic Acids pharmacology, Proline analogs & derivatives, Tacrolimus Binding Protein 1A metabolism
Abstract

Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.

Published
2003
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2. Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands.

Author

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, and Hamilton GS

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

Published
2002
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3. Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects.

Author

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, and Steiner JP

Subjects
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Administration, Oral, Amides chemistry, Amides pharmacology, Animals, Corpus Striatum enzymology, Corpus Striatum pathology, Corpus Striatum ultrastructure, Dopamine Agents, Immunohistochemistry, Ligands, Mice, Molecular Mimicry, 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 chemistry, Pipecolic Acids pharmacology, Proline chemistry, Proline pharmacology, Structure-Activity Relationship, Substantia Nigra enzymology, Substantia Nigra pathology, Substantia Nigra ultrastructure, Sulfhydryl Compounds chemistry, Sulfhydryl Compounds pharmacology, Tacrolimus Binding Protein 1A chemistry, Tyrosine 3-Monooxygenase metabolism, Amides chemical synthesis, Nerve Regeneration drug effects, Pipecolic Acids chemical synthesis, Proline analogs & derivatives, Proline chemical synthesis, Sulfhydryl Compounds chemical synthesis, Tacrolimus Binding Protein 1A antagonists & inhibitors
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.

Published
2002
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4. Use of parallel-synthesis combinatorial libraries for rapid identification of potent FKBP12 inhibitors.

Author

Choi C, Li JH, Vaal M, Thomas C, Limburg D, Wu YQ, Chen Y, Soni R, Scott C, Ross DT, Guo H, Howorth P, Valentine H, Liang S, Spicer D, Fuller M, Steiner J, and Hamilton GS

Subjects
Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Kinetics, Models, Molecular, Molecular Conformation, Pipecolic Acids chemical synthesis, Pipecolic Acids pharmacology, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides pharmacology, Urea chemical synthesis, Urea pharmacology, Combinatorial Chemistry Techniques methods, Enzyme Inhibitors chemical synthesis, Tacrolimus Binding Protein 1A antagonists & inhibitors, Urea analogs & derivatives
Abstract

Using simple, inexpensive equipment, we have used solution-phase parallel synthesis to rapidly prepare hundreds of sulfonamide- and urea-containing FKBP inhibitors, resulting in rapid identification of extremely potent compounds in these series.

Published
2002
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