Discovery of T-type Calcium Channel Antagonists from Multicomponent Reactions and Their Application in Paclitaxel-induced Peripheral Neuropathy

从多组分反应中发现T型钙通道拮抗剂及其在紫杉醇诱导的周围神经病变中的应用

• 批准号: 9552022
• 负责人: Rajesh Khanna
• 金额: $ 34.15万
• 依托单位: REGULONIX, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552022
• 关键词: Address; Afferent Neurons; American; Amitriptyline; Analgesics; Antidepressive Agents; Antineoplastic Agents; Arizona; Axon; Baclofen; Behavior; Biological Assay; Breast; Cancer Patient; Cell-Mediated Cytolysis; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Clinical Trials; Complex; Complication; Development; Disclosure; Dose; Dose-Limiting; Drug Kinetics; Drug Targeting; Dysesthesias; Esthesia; Feeling; Goals; Hand; Human; In Vitro; Ion Channel; Ketamine; Laboratories; Lead; Leukopenia; Long-Term Effects; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Mediator of activation protein; Medical; Medicine; Muscle relaxants; Neuraxis; Neurons; Norepinephrine; Numbness; Opioid; Ovarian; Overweight; Paclitaxel; Pain; Pain management; Paresthesia; Pathogenesis; Pathway interactions; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Personal Satisfaction; Pharmaceutical Preparations; Phase; Platinum Compounds; Property; Quality of life; Rattus; Reaction; Regimen; Safety; Sensory; Serotonin; Site; Specificity; Spinal; Spinal Cord; Spinal Ganglia; Structure; Symptoms; T-Type Calcium Channels; Technology; Testing; Therapeutic; Translating; Universities; Vinca Alkaloids; Work; addiction; analog; base; biophysical properties; cancer therapy; chemotherapeutic agent; chemotherapy; chronic pain; chronic painful condition; compliance behavior; design; dorsal horn; duloxetine; effective therapy; foot; improved; in vivo; inhibitor/antagonist; invention; meetings; neuronal excitability; neurotoxicity; neurotransmission; non-opioid analgesic; novel; novel therapeutics; opioid use; pain model; pain relief; pain signal; painful neuropathy; pre-clinical; preclinical study; reuptake; sensory stimulus; side effect; small molecule; somatosensory; success; taxane; venlafaxine; voltage

Summary Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is detected in 64% of cancer patients during all phases of cancer. Sensory symptoms in the hands and/or feet, typically in a “stocking-glove” pattern, are common, and manifested as pain, numbness, and/or tingling. CIPN can result in chemotherapy dose reduction or discontinuation, and can also have long-term effects on the quality of life. The course of CIPN can be unpredictable: while symptoms may resolve after chemotherapy is discontinued, they can also continue for years. Since its introduction in the 1970s, the antimicrotubule Paclitaxel (Taxol®) has been used as an effective anticancer agent against lung, breast, ovarian, leukopenia and liver cancer. But, Paclitaxel-induced peripheral neuropathy is the major dose-limiting side effect of paclitaxel. Taxanes (like Paclitaxel) may cause structural damage to peripheral nerves, resulting in aberrant somatosensory processing in the peripheral and/or central nervous system. Dorsal root ganglia (DRG) sensory neurons as well as neuronal cells in the spinal cord are key sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes dysregulation of ion channels. For example, Paclitaxel increases expression of low-voltage activated T-type (Cav3.2) Ca2+ channels in rat DRG neurons; these neurons are responsible for conveying noxious sensory stimuli, suggesting these channels are important mediators of specific sensory abnormalities associated with CIPN. T-type Ca2+ channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Though Cav3.2 has been targeted clinically with small molecule antagonists, no drugs targeting these channels have advanced to phase II human clinical trials. This proposal aims to explore multicomponent reaction products, developed in the laboratory of the PI - Dr. Jun Wang, for the rapid identification of potent and selective T-type Ca2+ channel antagonists. For this work, we have partnered with Dr. Rajesh Khanna (PI and Chief Scientific Officer, Regulonix, LLC) for characterizing select compounds and their analogs in in vitro and in vivo efficacy assays as well PK optimization. The work proposed here is the first step in developing non-opioid pain treatments for CIPN. We anticipate success against paclitaxel-induced chronic pain will translate into other chronic pain types as well, but CIPN provides focus for early stage proof-of-concept. Regulonix's specific aims are: (1) Design and synthesis of UAWJ111 analogs and elucidation of channel specificity and biophysical properties of select UAWJs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells; (2) Profile the in vitro cellular cytotoxicity and pharmacokinetic properties of UAWJ111 analogs; (3) Characterize the best two UAWJs, from Aim 2, for preclinical studies using a neuropathic pain model (paclitaxel) to provide information about efficacy. At the conclusion of our study, we expect to have a validated UAWJ analog and several worthy backup compounds.

摘要摘要 ：化疗所致周围神经病变在各期癌症患者中均可检出 癌症的威胁。手和/或脚的感觉性症状是常见的，通常是“袜子手套”模式，以及 表现为疼痛、麻木和/或刺痛。CIPN可导致化疗剂量减少或 停药，也可能对生活质量产生长期影响。CIPN的课程可以是 不可预测：虽然停止化疗后症状可能会缓解，但它们也可以持续 好几年了。自20世纪70年代推出以来，抗微管紫杉醇(Taxol®)一直被用作 针对肺癌、乳腺癌、卵巢癌、白细胞减少症和肝癌的有效抗癌药物。但是，紫杉醇诱导 周围神经病变是紫杉醇的主要剂量限制性副作用。紫杉烷(如紫杉醇)可能会导致 周围神经的结构性损伤，导致周围神经的躯体感觉异常处理 和/或中枢神经系统。背根神经节(DRG)感觉神经元和神经元 脊髓是化疗所致神经毒性发生的关键部位。发病机制很复杂，但 包括离子通道的失调。例如，紫杉醇增加了低电压激活的表达 大鼠背根神经节神经元的T型(Cav3.2)钙通道；这些神经元负责传递伤害性物质 感觉刺激，表明这些通道是特定感觉异常的重要媒介 与CIPN关联。T型钙通道是神经元兴奋性增强的关键决定因素 伴随持续性神经病理性疼痛的神经传递。尽管Cav3.2已经成为临床上的靶点 小分子拮抗剂，没有针对这些通道的药物进入第二阶段的人类临床试验。 这项建议旨在探索在Pi-Dr.Jun的实验室开发的多组分反应产物 Wang，用于快速鉴定有效和选择性的T型钙通道拮抗剂。对于这项工作，我们 与Rajesh Khanna博士(PI兼Regulonix，LLC首席科学官)合作 筛选出化合物及其类似物，进行体内外药效试验和PK优化。这项工作 这里提出的是开发非阿片类疼痛治疗CIPN的第一步。我们期待着成功 抗紫杉醇诱导的慢性疼痛也会转化为其他慢性疼痛类型，但CIPN提供了 重点关注早期概念验证。Regulonix的具体目标是：(1)UAWJ111的设计和合成 类比和阐明部分UAWJ的通道特异性和生物物理特性以获得机制 和安全信息，并记录相关神经细胞的独特功能途径；(2)轮廓 UAWJ111类似物的体外细胞毒性和药代动力学特性 来自AIM 2的两个UAWJ，用于使用神经病理性疼痛模型(紫杉醇)进行临床前研究，以提供 有关功效的信息。在我们的研究结束时，我们希望有一个经过验证的UAWJ模拟和 几种有价值的备用化合物。