Document Report Card

ID: ALA1145039

Journal: J Med Chem

Title: Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor.

Authors: Majer P, Jackson PF, Delahanty G, Grella BS, Ko YS, Li W, Liu Q, Maclin KM, Poláková J, Shaffer KA, Stoermer D, Vitharana D, Wang EY, Zakrzewski A, Rojas C, Slusher BS, Wozniak KM, Burak E, Limsakun T, Tsukamoto T.

Abstract: A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

CiteXplore: 12723961

DOI: 10.1021/jm020515w