title: Synthesis, molecular modeling and biological evaluation of aza-proline and aza-pipecolic derivatives as FKBP12 ligands and their in vivo neuroprotective effects.
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.
authors.affiliation: Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, MD 21224, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Wilkinson
authors.forename: Bert E
authors.initials: BE
authors.lastname: Thomas
authors.forename: David C
authors.initials: DC
authors.lastname: Limburg
authors.forename: Agnes
authors.initials: A
authors.lastname: Holmes
authors.forename: Hansjorg
authors.initials: H
authors.lastname: Sauer
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Ross
authors.forename: Raj
authors.initials: R
authors.lastname: Soni
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Pamela
authors.initials: P
authors.lastname: Howorth
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: Dawn
authors.initials: D
authors.lastname: Spicer
authors.forename: Mike
authors.initials: M
authors.lastname: Fuller
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hamilton
authors.forename: Yong-Qian
authors.initials: YQ
authors.lastname: Wu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D008024:Ligands; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D011392:Proline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D022061:Tacrolimus Binding Protein 1A; C031345:pipecolic acid