Majer, Pavel Hin, Bunda Stoermer, Doris Adams, Jessica Xu, Weizheng Duvall, Bridget R. Delahanty, Greg Liu, Qun Stathis, Marigo J. M. Wozniak, Krystyna Slusher, Barbara S. Tsukamoto, Takashi 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). Glutamate Carboxypeptidase II;GCP II inhibitor;CCI;MPPA;glutamate carboxypeptidase II;acid;Subsequent SAR studies;compounds 6 c;IC 50 value;GCP II 2006-05-18
    https://acs.figshare.com/articles/journal_contribution/Structural_Optimization_of_Thiol_Based_Inhibitors_of_Glutamate_Carboxypeptidase_II_by_Modification_of_the_P1_Side_Chain/3221641
10.1021/jm051019l.s001