Synthesis, molecular modeling and biological evaluation of aza-proline and aza-pipecolic derivatives as FKBP12 ligands and their in vivo neuroprotective effects.
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.
Wilkinson
Douglas E
DE
Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, MD 21224, USA.
Thomas
Bert E
BE
Limburg
David C
DC
Holmes
Agnes
A
Sauer
Hansjorg
H
Ross
Douglas T
DT
Soni
Raj
R
Chen
Yi
Y
Guo
Hong
H
Howorth
Pamela
P
Valentine
Heather
H
Spicer
Dawn
D
Fuller
Mike
M
Steiner
Joseph P
JP
Hamilton
Gregory S
GS
Wu
Yong-Qian
YQ
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
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