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
Peptidylprolyl isomerase cyclophilins play critical roles in a variety of biological processes. Recent findings that cyclophilins are present at high levels in the CNS and that cyclosporin A may possess neuroprotective/neurotrophic effects have prompted us to search for nonimmunosuppressant small molecule cyclophilin ligands. To this end, we report the lead identification through "virtual screening" and the synthesis of our first series of non-peptidic cyclophilin ligands, along with the preliminary biological results.
