Enantiospecificity of glutamate carboxypeptidase II inhibition.
Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.
Tsukamoto
Takashi
T
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland 21224, USA. tsukamoto@guilfordpharm.com
Majer
Pavel
P
Vitharana
Dilrukshi
D
Ni
Chiyou
C
Hin
Bunda
B
Lu
Xi-Chun M
XC
Thomas
Ajit G
AG
Wozniak
Krystyna M
KM
Calvin
David C
DC
Wu
Ying
Y
Slusher
Barbara S
BS
Scarpetti
David
D
Bonneville
George W
GW
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003251:Constriction, Pathologic / Q000150:complications; D018360:Crystallography, X-Ray; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005977:Glutarates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046509:Tissue Culture Techniques; D005466:Fluorocarbons
D000700:Analgesics; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates; D007770:L-Lactate Dehydrogenase; D018696:Neuroprotective Agents; D010721:Phosphinic Acids; D013438:Sulfhydryl Compounds; C474576:2-(3-mercaptopropyl)pentanedioic acid; C500159:2-(hydroxypentafluorophenylmethylphosphinoylmethyl)pentanedioic acid; D005466:Fluorocarbons