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

• Published in: Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (13), p.2097-2100
• Main Authors: Stoermer, Doris, Liu, Qun, Hall, Monicia R, Flanary, Juliet M, Thomas, Ajit G, Rojas, Camilo, Slusher, Barbara S, Tsukamoto, Takashi
• Format: Article
• Language: English
• Subjects: Aeromonas - enzymology; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glutamate Carboxypeptidase II - antagonists & inhibitors; Glutamate Carboxypeptidase II - chemistry; Hydrolases; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - pharmacology; Indicators and Reagents; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00407-4

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 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. Graphic