TY - JOUR
T1 - Enantiospecificity of glutamate carboxypeptidase II inhibition
AU - Tsukamoto, Takashi
AU - Majer, Pavel
AU - Vitharana, Dilrukshi
AU - Ni, Chiyou
AU - Hin, Bunda
AU - Lu, Xi Chun M.
AU - Thomas, Ajit G.
AU - Wozniak, Krystyna M.
AU - Calvin, David C.
AU - Wu, Ying
AU - Slusher, Barbara S.
AU - Scarpetti, David
AU - Bonneville, George W.
PY - 2005/4/7
Y1 - 2005/4/7
N2 - 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-(hydroxyphosphinoyl-methyl) 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.
AB - 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-(hydroxyphosphinoyl-methyl) 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.
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U2 - 10.1021/jm049258g
DO - 10.1021/jm049258g
M3 - Article
C2 - 15801825
AN - SCOPUS:20244368510
SN - 0022-2623
VL - 48
SP - 2319
EP - 2324
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -