Document Report Card

ID: ALA2150994

Journal: J Med Chem

Title: Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds.

Authors: Stoermer D, Vitharana D, Hin N, Delahanty G, Duvall B, Ferraris DV, Grella BS, Hoover R, Rojas C, Shanholtz MK, Smith KP, Stathis M, Wu Y, Wozniak KM, Slusher BS, Tsukamoto T.

Abstract: A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylic acid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

CiteXplore: 22642259

DOI: 10.1021/jm300488m