GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）是与抗癌治疗相关的常见毒性，可导致早期停药和/或严重影响生活质量。关于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方法。谷氨酸过度传递与周围神经病变和神经性疼痛的发病机制有关。神经胶质酶谷氨酸羧肽酶II （GCPII）的抑制已被证明可以选择性地抑制谷氨酸的过度传递，减轻神经性疼痛，保护周围神经免受化疗药物引起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硫醇基GCPII抑制剂被纳入临床研究。尽管该抑制剂在1期试验中耐受性良好，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。作为一类药物，硫醇类药物有诱发超敏反应的风险。我们现在概述了一个迭代的药物发现计划，以确定临床可行的非硫醇GCPII抑制剂，以测试假设

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.