Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II

Doris Stoermer; Qun Liu; Monicia R. Hall; Juliet M. Flanary; Ajit G. Thomas; Camilo Rojas; Barbara S. Slusher; Takashi Tsukamoto

doi:10.1016/S0960-894X(03)00407-4

Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II

Doris Stoermer, Qun Liu, Monicia R. Hall, Juliet M. Flanary, Ajit G. Thomas, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1′ residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC₅₀ value of 220 nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

Original language	English (US)
Pages (from-to)	2097-2100
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	13
Issue number	13
DOIs	https://doi.org/10.1016/S0960-894X(03)00407-4
State	Published - Jul 7 2003
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/S0960-894X(03)00407-4

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title = "Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II",

abstract = "A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1′ residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC50 value of 220 nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.",

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T1 - Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II

AU - Stoermer, Doris

AU - Liu, Qun

AU - Hall, Monicia R.

AU - Flanary, Juliet M.

AU - Thomas, Ajit G.

AU - Rojas, Camilo

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

PY - 2003/7/7

Y1 - 2003/7/7

N2 - A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1′ residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC50 value of 220 nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

AB - A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1′ residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC50 value of 220 nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

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ER -

Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II

Abstract

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