GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy

GCPII 抑制剂用于治疗化疗引起的神经病变

• 批准号: 8468134
• 负责人: Barbara Stauch Slusher
• 金额: $ 34.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-09 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468134
• 关键词: Adverse effects; Adverse event; Affect; Amides; Animal Model; Area; Attenuated; Axon; Back; Binding; Bioavailable; Biological Assay; Biological Availability; Biological Markers; Cancer Patient; Cancer Survivor; Cells; Chemicals; Clinical Research; Clinical Trials; Complex; Data; Development; Dose; Drug Kinetics; Ensure; Enzymes; Evaluation; Evidence based treatment; Exhibits; Generations; Glutamate Carboxypeptidase II; Glutamates; Half-Life; Hypersensitivity; In Vitro; Inhibitory Concentration 50; Injury; Knockout Mice; Knowledge; Lead; Length; Liver Microsomes; Medical; Metabolic; Metalloproteases; Modeling; Nerve Crush; Neural Conduction; Neuroglia; Neuropathy; Nitrogen; Oral; Paclitaxel; Pain; Pathogenesis; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral nerve injury; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Preclinical Drug Evaluation; Primates; Prodrugs; Quality of life; Rattus; Reaction; Research; Risk; Rodent; Scheme; Severities; Signal Transduction; Skin Tissue; Spinal Cord; Structure; Sulfhydryl Compounds; Sulfonamides; Surveys; Symptoms; Testing; Therapeutic; Therapeutic Clinical Trial; Tissues; Toxic effect; Urea; Zinc; allodynia; anticancer treatment; base; carboxylate; chemotherapeutic agent; chemotherapy; chemotherapy induced neuropathy; drug discovery; drug metabolism; hydroxamate; in vivo; inhibitor/antagonist; meetings; myelination; neoplastic; novel; oxaliplatin; painful neuropathy; pharmacophore; phosphonate; prevent; receptor; research study; scaffold; sciatic nerve; transmission process

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.

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，可导致治疗提前停止和/或严重影响生活质量。人们对 CIPN 的机制知之甚少，尽管有许多 CIPN 治疗临床试验，但不存在标准的循证治疗。过量的谷氨酸传输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) 已被证明可以选择性抑制过量的谷氨酸传输，减轻神经性疼痛，并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、基于硫醇的 GCPII 抑制剂被纳入临床研究。尽管该抑制剂在第一阶段的耐受性良好，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开发。重要的是，毒性不是由 GCPII 机制引起的，而是由化合物中的硫醇部分引起的。作为一类，硫醇药物有诱发过敏反应的风险。我们现在概述了一个迭代药物发现计划，以确定临床上可行的非硫醇 GCPII 抑制剂，以检验以下假设： 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换策略、广泛的体外药性评估、药物代谢、体内药代动力学、生物标志物策略以及紫杉醇和奥沙利铂诱导的神经病变和神经挤压功效实验中的化合物评估。这些努力中产生的活性化合物将为 IND 进行研究并最终在 CIPN 患者中进行临床研究做好准备。