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.
Department of Research, Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. wuy@guilfordpharm.com
Yong-Qian
YQ
Wu
Douglas E
DE
Wilkinson
David
D
Limburg
Jia-He
JH
Li
Hansjorg
H
Sauer
Doug
D
Ross
Shi
S
Liang
Dawn
D
Spicer
Heather
H
Valentine
Mike
M
Fuller
Hong
H
Guo
Pam
P
Howorth
Raj
R
Soni
Yi
Y
Chen
Joseph P
JP
Steiner
Gregory S
GS
Hamilton
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