Structural Optimization of Thiol-Based Inhibitors of Glutamate Carboxypeptidase II by Modification of the P1‘ Side Chain

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 <b>6c</b> was found to be the most potent inhibitor with an IC<sub>50</sub> 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 phenylsulfanyl analogues of <b>6c</b>, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid <b>26a</b> and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid <b>26b</b>, also possess potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic pain, compounds <b>6c</b> and <b>26a</b> significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).