GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy

描述(申请人提供)：化疗引起的周围神经病(CIPN)是一种与抗癌治疗相关的常见毒性，可导致早期停止治疗和/或严重影响生活质量。人们对CIPN的发病机制知之甚少，尽管进行了许多CIPN治疗临床试验，但尚无标准的循证治疗方法。谷氨酸过度传递与周围神经病和神经病理性疼痛的发病机制有关。抑制神经胶质酶谷氨酸羧基肽酶II(GCPII)可以选择性地抑制谷氨酸过度传递，减轻神经病理性疼痛，保护周围神经免受化疗药物所致的功能和组织学损伤。基于这些数据，一种口服生物利用型硫醇类GCPII抑制剂被应用于临床研究。尽管该抑制剂在第一阶段耐受性良好，但随后在GLP灵长类研究中观察到的免疫毒性阻止了它的开发。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，硫醇类药物有诱发过敏反应的风险。我们现在概述一个迭代的药物发现计划，以确定临床上可行的非硫醇GCPII抑制剂，以检验以下假设 这一机制将为CIPN患者提供治疗上的好处。我们的迭代药物发现计划包括系统的锌结合基团替换策略、广泛的体外药物能力评估、药物代谢、体内药代动力学、生物标记物策略，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对化合物的评估。从这些努力中出现的活性化合物将准备好用于IND使能研究，并最终在CIPN患者中进行临床研究。 公共卫生相关性：化疗引起的周围神经病(CIPN)是化疗的一种痛苦和常见的副作用，癌症幸存者将其评为最致残的副作用之一。人们对CIPN的发病机制知之甚少，尽管进行了许多CIPN治疗临床试验，但尚无标准的循证治疗方法。在几种动物模型中，胶质酶谷氨酸羧基肽酶II(GCPII)的抑制剂已被证明可以保护周围神经免受化疗所致的损伤，防止神经病理性疼痛症状，而不影响化疗效果。我们建议合成有效的、选择性的、口服的和组织可穿透的GCPII抑制剂，当与化疗同时给药时，将减轻CIPN的严重程度。通过这些努力产生的药物将准备好用于IND使能研究，并最终在CIPN患者中进行临床研究。

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. PUBLIC HEALTH RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and common side effect of chemotherapy treatment rated by cancer survivors as one of the most disabling. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. In several animal models, inhibitors of the glial enzyme glutamate carboxypeptidase II (GCPII) have been shown to protect peripheral nerves from chemotherapy-induced injury and prevent neuropathic pain symptoms, without affecting chemotherapy efficacy. We propose to synthesize potent, selective, orally available, and tissue penetrable GCPII inhibitors that when dosed concurrently with chemotherapy will attenuate CIPN severity. Drugs emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients.