Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects.
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.
Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, MD 21224, USA.
Gregory S
GS
Hamilton
Yong-Qian
YQ
Wu
David C
DC
Limburg
Douglas E
DE
Wilkinson
Mark J
MJ
Vaal
Jia-He
JH
Li
Christine
C
Thomas
Wei
W
Huang
Hansjorg
H
Sauer
Douglas T
DT
Ross
Raj
R
Soni
Yi
Y
Chen
Hongshi
H
Guo
Pamela
P
Howorth
Heather
H
Valentine
Shi
S
Liang
Dawn
D
Spicer
Mike
M
Fuller
Joseph P
JP
Steiner
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D015259:Dopamine Agents; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D018716:Molecular Mimicry; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; 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; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000577:Amides; D015259:Dopamine Agents; D008024:Ligands; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D013438:Sulfhydryl Compounds; D011392:Proline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D022061:Tacrolimus Binding Protein 1A