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.
Hamilton
Gregory S
GS
Department of Research, Guilford Pharmaceuticals, Inc., Baltimore, MD 21224, USA.
Wu
Yong-Qian
YQ
Limburg
David C
DC
Wilkinson
Douglas E
DE
Vaal
Mark J
MJ
Li
Jia-He
JH
Thomas
Christine
C
Huang
Wei
W
Sauer
Hansjorg
H
Ross
Douglas T
DT
Soni
Raj
R
Chen
Yi
Y
Guo
Hongshi
H
Howorth
Pamela
P
Valentine
Heather
H
Liang
Shi
S
Spicer
Dawn
D
Fuller
Mike
M
Steiner
Joseph P
JP
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