title: The orally active glutamate carboxypeptidase II inhibitor E2072 exhibits sustained nerve exposure and attenuates peripheral neuropathy.
abstract: Peripheral neuropathy from nerve trauma is a significant problem in the human population and often constitutes a dose-limiting toxicity in patients receiving chemotherapy. (3-2-Mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) is a potent (K(i) = 10 nM), selective, and orally available inhibitor of glutamate carboxypeptidase II (GCPII). Here, we report that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatin-induced neuropathy. In the chronic constrictive injury model, orally administered E2072 reversed pre-existing thermal hyperalgesia in rats in a dose-dependent fashion with a minimally effective dose of 0.1 mg/kg/day. It is noteworthy that multiple days of dosing of E2072 were required before analgesia was realized even though GCPII inhibitory exposures were achieved on the first day of dosing. In addition, analgesia was found to persist for up to 7 days after cessation of dosing, consistent with E2072's pharmacokinetic profile and sustained exposure. Furthermore, in a chronic oxaliplatin-induced neuropathy model (6 mg/kg i.p. oxaliplatin twice weekly for 4 weeks), female BALB/c mice receiving daily oral E2072 at 1.0 and 0.1 mg/kg displayed no deficits in either caudal or digital velocity compared with significant deficits observed in mice treated with oxaliplatin alone (12 ± 3 and 9 ± 2%, respectively). Similar findings were seen with oxaliplatin-induced digital and caudal amplitude deficits. It is noteworthy that E2072 showed no interference with the antineoplastic efficacy of oxaliplatin in mice bearing leukemia (L1210), even at doses 100 times its neuroprotective/analgesic dose, indicating a selective effect on neuropathy. These data support the therapeutic utility of GCPII inhibitors in neuropathy and neuropathic pain.
authors.affiliation: Brain Science Institute, NeuroTranslational Drug Discovery Program, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: James J
authors.initials: JJ
authors.lastname: Vornov
authors.forename: Rena
authors.initials: R
authors.lastname: Lapidus
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D009431:Neural Conduction / Q000187:drug effects*; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: C577642:3-(2-mercaptoethyl)biphenyl-2,3-dicarboxylic acid; D000970:Antineoplastic Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D000077150:Oxaliplatin; D043425:Glutamate Carboxypeptidase II