Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands.
The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.
Wu
Yong-Qian
YQ
Department of Research, Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. wuy@guilfordpharm.com
Wilkinson
Douglas E
DE
Limburg
David
D
Li
Jia-He
JH
Sauer
Hansjorg
H
Ross
Doug
D
Liang
Shi
S
Spicer
Dawn
D
Valentine
Heather
H
Fuller
Mike
M
Guo
Hong
H
Howorth
Pam
P
Soni
Raj
R
Chen
Yi
Y
Steiner
Joseph P
JP
Hamilton
Gregory S
GS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D015259:Dopamine Agents; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; 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; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry
D015259:Dopamine Agents; D007659:Ketones; D008024:Ligands; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D013438:Sulfhydryl Compounds; D011392:Proline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D022061:Tacrolimus Binding Protein 1A