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J Med Chem ; 55(12): 5922-32, 2012 Jun 28.
Article in English | MEDLINE | ID: mdl-22642259

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.


Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glutamate Carboxypeptidase II/antagonists & inhibitors , Animals , Benzoates/pharmacokinetics , Benzoates/therapeutic use , Chemistry Techniques, Synthetic , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Neuralgia/drug therapy , Rats
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