gpi-5693 and Neuralgia

δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.

Topics: Animals; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Lactones; Microsomes, Liver; Neuralgia; Prodrugs; Rats

Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.

Topics: Animals; Area Under Curve; Biological Availability; Constriction, Pathologic; Dose-Response Relationship, Drug; Glutamate Carboxypeptidase II; Glutarates; Half-Life; Hot Temperature; Hyperalgesia; Male; Motor Activity; Neuralgia; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds

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.

Topics: Animals; Benzoates; Chemistry Techniques, Synthetic; Drug Design; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Humans; Inhibitory Concentration 50; Neuralgia; Rats