Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain.

  title={Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain.},
  author={Pavel Majer and Bunda Hin and Doris Stoermer and Jessica Adams and Weizhen Xu and Bridget R Duvall and Greg Delahanty and Qun Liu and Marigo J Stathis and Krystyna M. Wozniak and Barbara S. Slusher and Takashi Tsukamoto},
  journal={Journal of medicinal chemistry},
  volume={49 10},
A series of thiol-based inhibitors containing a benzyl moiety at the P1' position have been synthesized and tested for their abilities to inhibit glutamate carboxypeptidase II (GCP II). 3-(2-Carboxy-5-mercaptopentyl)benzoic acid 6c was found to be the most potent inhibitor with an IC(50) value of 15 nM, 6-fold more potent than 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), a previously discovered, orally active GCP II inhibitor. Subsequent SAR studies have revealed that the phenoxy and… Expand
Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds.
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These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCP II active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate. Expand
Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity.
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Human glutamate carboxypeptidase II inhibition: structures of GCPII in complex with two potent inhibitors, quisqualate and 2-PMPA.
Crystal structures were determined of the extracellular part of GCPII in complex with two potent inhibitors, quisqualate and 2-PMPA, and models were constructed for binding of the inhibitors willardiine, homoibotenate, L-2-amino-4-phosphonobutanoic acid and L-serine-O-sulfate to the S1' site of the enzyme. Expand
Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity.
Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket, providing a mechanistic explanation for the structure-activity relationship data. Expand
Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II.
Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be neuroprotective in multiple preclinical models in which dysregulated glutamatergic transmission is implicated. Herein, weExpand
Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs.
The S1 pocket of GCPII could be accurately defined and analyzed for the first time, and the data indicate the importance of Asn519, Arg463, Arg534, and Arg536 for recognition of the penultimate substrate residues, as well as mechanistic explanation of G CPII preference for acidic dipeptides. Expand
δ-Thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors.
Thiolactones derived from thiol-based glutamate carboxypeptidase II inhibitors exhibited efficacy in a rat model of neuropathic pain following oral administration, consistent with the oral plasma pharmacokinetics. Expand
Mapping of the active site of glutamate carboxypeptidase II by site‐directed mutagenesis
The experimental results suggest that the amino acid residues delineating the S1′ pocket of the enzyme (namely Arg210) contribute primarily to the high affinity binding of GCPII substrates/inhibitors, whereas the residues forming the S 1 pocket might be more important for the ‘fine‐tuning’ of G CPII substrate specificity. Expand
Glutamate Carboxypeptidase II : An Overview of Structural Studies and Their Importance for Structure-Based Drug Design and Deciphering the Reaction Mechanism of the Enzyme
Recent years witnessed rapid expansion of our knowledge about structural features of human glutamate carboxypeptidase II (GCPII). There are over thirty X-ray structures of human GCPII (and of itsExpand