Design, Synthesis, and Pharmacological Evaluation of Glutamate Carboxypeptidase II (GCPII) Inhibitors Based on Thioalkylbenzoic Acid Scaffolds
Journal of Medicinal Chemistry2012Vol. 55(12), pp. 5922–5932
Citations Over TimeTop 19% of 2012 papers
Doris Stoermer, Dilrukshi Vitharana, Niyada Hin, Greg Delahanty, Bridget Duvall, Dana Ferraris, Brian Grella, Randall Hoover, Camilo Rojas, Megan K. Shanholtz, Kyle P. Smith, Marigo Stathis, Ying Wu, Krystyna M. Wozniak, Barbara S. Slusher, Takashi Tsukamoto
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.
Related Papers
- → N-acetylaspartylglutamate (NAAG) and glutamate carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications(2019)71 cited
- → GCPII Imaging and Cancer(2012)78 cited
- → Structure-Activity Relationships of Glutamate Carboxypeptidase II (GCPII) Inhibitors(2012)42 cited
- → Design of Highly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carboxypeptidase II(2015)31 cited
- → 228 Effect of Benzoic Acid Feeding Strategy on Weanling Pig Growth Performance(2023)