jm051019l_si_001.pdf (10.21 kB)
Structural Optimization of Thiol-Based Inhibitors of Glutamate Carboxypeptidase II by Modification of the P1‘ Side Chain
journal contribution
posted on 2006-05-18, 00:00 authored by Pavel Majer, Bunda Hin, Doris Stoermer, Jessica Adams, Weizheng Xu, Bridget R. Duvall, Greg Delahanty, Qun Liu, Marigo J. Stathis, Krystyna M. Wozniak, Barbara S. Slusher, Takashi TsukamotoA 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 IC50 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 6c, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid 26a and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid 26b, also possess
potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic
pain, compounds 6c and 26a significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).