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.
Subject(s)
Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Pipecolic Acids/chemical synthesis , Pipecolic Acids/pharmacology , Proline/analogs & derivatives , Tacrolimus Binding Protein 1A/metabolism , 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/metabolismABSTRACT
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.
Subject(s)
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 , 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/metabolismABSTRACT
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.
Subject(s)
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 , 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/chemistryABSTRACT
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.
Subject(s)
Combinatorial Chemistry Techniques/methods , Enzyme Inhibitors/chemical synthesis , Tacrolimus Binding Protein 1A/antagonists & inhibitors , Urea/analogs & derivatives , 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/pharmacologyABSTRACT
In parallel with our work on solution-phase parallel synthesis of ligands for the rotamase enzyme FKBP12, we herein report a methodology for the solid-phase synthesis of two classes of inhibitor, N-sulfonyl and N-carbamoylprolyl and pipecolyl amides along with their in vitro/in vivo biological results.
