GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy

描述（由申请方提供）：化疗诱导的周围神经病变（CIPN）是一种与抗癌治疗相关的常见毒性，可导致提前停止治疗和/或严重影响生活质量。对CIPN的机制知之甚少，尽管有许多CIPN治疗性临床试验，但没有标准的循证治疗。过量的谷氨酸传递与周围神经病变和神经性疼痛的发病机制有关。抑制神经胶质酶谷氨酸羧肽酶II（GCPII）已显示出选择性地抑制过量的谷氨酸传递和减轻神经性疼痛，并保护周围神经免受化疗药物诱导的功能和组织学缺陷。基于这些数据，一种口服生物可利用的基于巯基的GCPII抑制剂被纳入临床研究。尽管该抑制剂在I期研究中耐受良好，但随后在GLP灵长类动物研究中观察到的免疫毒性阻止了其发展。重要的是，毒性不是由于GCPII机制，而是由于化合物中的硫醇部分。作为一类，硫醇类药物具有诱导超敏反应的风险。我们现在概述了一个迭代的药物发现计划，以确定临床上可行的非巯基GCPII抑制剂，以测试假设， 该机制将为CIPN患者提供治疗益处。我们的迭代药物发现计划包括系统的锌结合基团替代策略，广泛的体外药物能力评估，药物代谢，体内药代动力学，生物标志物策略，以及在紫杉醇和奥沙利铂诱导的神经病变和神经挤压疗效实验中评价化合物。从这些努力中产生的活性化合物将准备用于IND使能研究，并最终用于CIPN患者的临床研究。

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with anticancer treatment which can lead to early discontinuation of therapy and/or severely affect quality of life. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. Excessive glutamate transmission has been implicated in the pathogenesis of peripheral neuropathy and neuropathic pain. Inhibition of the glial enzyme glutamate carboxypeptidase II (GCPII) has been shown to selectively dampen excessive glutamate transmission and alleviate neuropathic pain and protect peripheral nerves from the functional and histological deficits induced by chemotherapeutic agents. Based on these data, an orally bioavailable, thiol-based GCPII inhibitor was taken into clinical studies. Although the inhibitor was well-tolerated in Phase 1, subsequent immunological toxicities observed in GLP primate studies halted its development. Importantly the toxicity was not due to the GCPII mechanism, but rather due to the thiol moiety in the compound. As a class, thiol drugs have a risk of inducing hypersensitivity reactions. We now outline an iterative drug discovery plan to identify clinically viable non thiol GCPII inhibitors to test the hypothesis that this mechanism will provide therapeutic benefit to CIPN patients. Our iterative drug discovery plan includes a systematic zinc binding group replacement strategy, extensive in vitro drug-ability assessments, drug metabolism, in vivo pharmacokinetics, biomarker strategies, and evaluation of compounds in paclitaxel- and oxaliplatin-induced neuropathy and nerve crush efficacy experiments. Active compounds emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients.