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 IC(50) value of 220nM. 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.
authors.affiliation: Guilford Pharmaceuticals Inc., 6611 Tributary Street, MD 21224, Baltimore, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Stoermer
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.forename: Monicia R
authors.initials: MR
authors.lastname: Hall
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Flanary
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D000333:Aeromonas / Q000201:enzymology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D043425:Glutamate Carboxypeptidase II