Optimization of Betulinic Acid analogs for T-type calcium channel inhibition for non-addictive relief of chronic pain

用于 T 型钙通道抑制的桦木酸类似物的优化，用于非成瘾性缓解慢性疼痛

• 批准号: 9907601
• 负责人: Rajesh Khanna
• 金额: $ 22.47万
• 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/9907601
• 关键词: Absence of pain sensation; Affect; Afferent Neurons; American; Amitriptyline; Analgesics; Antidepressive Agents; Arizona; Axon; Baclofen; Betulinic Acid; Biological Assay; Calcium; Calcium Channel Blockers; Calcium Channel Inhibition; Cancer Patient; Cell-Mediated Cytolysis; Cells; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Clinical Trials; Complex; Complication; Coupled; Dose-Limiting; Drug Kinetics; Drug Targeting; Dysesthesias; Effectiveness; Esthesia; Feeling; Fiber; G-Protein-Coupled Receptors; Human; In Vitro; Indigenous; Ion Channel; Laboratories; Lavandula; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Medicinal Plants; Modeling; Muscle relaxants; Natural Products; Neuraxis; Neurons; Neuropathy; Norepinephrine; Numbness; Opiate Addiction; Opioid; Opioid Receptor; Oral; Paclitaxel; Pain; Pain management; Paresthesia; Pathogenesis; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plants; Platinum Compounds; Prevalence; Property; Protein Isoforms; Proteins; Quality of life; Rattus; Regimen; Regulation; Role; Safety; Sensory; Serotonin; Shock; Site; Southwestern United States; Specificity; Spinal; Spinal Cord; Spinal Ganglia; Structure; Survival Rate; T-Type Calcium Channels; Testing; Tissues; Translating; Treatment Protocols; Universities; Vinca Alkaloids; Work; addiction; analog; base; biophysical properties; cancer pain; cancer survival; cancer therapy; central sensitization; chemotherapeutic agent; chemotherapy; chronic pain; chronic pain relief; chronic painful condition; compliance behavior; counterscreen; design; dorsal horn; drug discovery; duloxetine; effective therapy; improved; in vivo; inhibitor/antagonist; meetings; neuronal excitability; neurotoxic; neurotoxicity; neurotransmission; non-opioid analgesic; novel; novel therapeutics; opioid misuse; opioid sparing; opioid use; pain model; pain relief; pain signal; painful neuropathy; preclinical study; reuptake; screening; sensory stimulus; side effect; small molecule; somatosensory; success; synaptic function; taxane; venlafaxine; voltage

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common (prevalence 30–70%) and potentially dose- limiting side effect of many cancer chemotherapy drug treatment regimens. Clinically, CIPN presents with pain that is burning, shooting or electric-shock-like. The increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large, unmet medical problem. Neurotoxic chemotherapeutic agents (e.g., antimicrotubule agents 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 the preferential sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes alterations in ion channels. Paclitaxel (Taxol®) increases T-type (Cav3.2) voltage-gated Ca2+ currents in rat dorsal root ganglion (DRG) neurons; these neurons are responsible for conveying noxious sensory stimuli, suggesting these channels are important mediators of specific sensory abnormalities associated with CIPN. Given the roles of these channels in regulating afferent fiber excitability and synaptic function in the spinal dorsal horn and their dynamic regulation during pain states, blocking or depleting Cav3.2 channels in these tissues should mediate analgesic effects. In the past 5 years, considerable effort has been applied towards identifying novel classes of T-type calcium channel blockers. This proposal aims to develop potent, orally available, and selective Cav3.2 channel antagonists, building on the structure of a natural product – betulinic acid (BA) – identified by the laboratory of Dr. Leslie Gunatilaka (Director, Natural Products Center, University of Arizona (UA)) and characterized by the PI Dr. Rajesh Khanna (UA) to be Cav3.2-selective and antinociceptive in CIPN. For this work, we have partnered with Regulonix, LLC for characterizing select Cav3.2-targeted compounds and their analogs in in vitro and in vivo efficacy assays as well as early ADME and PK optimization. The work proposed here is the first step in developing non-opioid pain treatments for CIPN that also curb opioid misuse and addiction. We anticipate success against paclitaxel-induced chronic pain to 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 (Dr. L. Gunatilaka) of BA analogues and elucidation of Cav3.2 specificity and biophysical properties of select BA analogs to gain mechanistic and safety information and to document the unique pathway for function in neurons; (2) Profile BA analogues for their in vitro cellular cytotoxicity, early ADME and pharmacokinetic properties, and screening for off-target effects on GPCRs, ion channels and alternative known pain targets, including opioid receptors; and (3) Characterize the best two BA analogs, from Aim 2, for preclinical studies using a neuropathic pain model (paclitaxel) to provide information about oral efficacy, safety, and opioid- sparing. Upon completion, we expect to have a validated BA analog and several worthy backup compounds.

抽象的 化疗引起的周围神经病变 (CIPN) 很常见（患病率 30-70%），并且可能与剂量有关 许多癌症化疗药物治疗方案的有限副作用临床上，CIPN 表现为疼痛。 癌症患病率的增加伴随着癌症发病率的增加。 化疗方案导致的癌症生存率正在将癌症疼痛转变为一个巨大的、未得到满足的医疗问题 神经毒性化疗药物（例如紫杉醇等抗微管药物）可能会导致结构性问题。 周围神经损伤，导致周围和/或中枢体感处理异常 神经系统中的背根神经节（DRG）感觉神经元以及脊髓中的神经元细胞。 化疗引起的神经毒性发生的优先位点 发病机制很复杂，但包括。 离子通道的改变。紫杉醇 (Taxol®) 增加大鼠 T 型 (Cav3.2) 电压门控 Ca2+ 电流。 背根神经节（DRG）神经元；这些神经元负责传递有害的感觉刺激， 表明这些通道是与 CIPN 相关的特定感觉异常的重要介质。 鉴于这些通道在调节脊髓背侧传入纤维兴奋性和突触功能中的作用 角及其在疼痛状态下的动态调节，阻断或耗尽这些组织中的 Cav3.2 通道 在过去的 5 年里，人们付出了巨大的努力来确定镇痛作用。 该提案旨在开发有效的、口服的、新型的 T 型钙通道阻滞剂。 选择性 Cav3.2 通道拮抗剂，基于天然产物桦木酸 (BA) 的结构 – 经 Leslie Gunatilaka 博士（亚利桑那大学天然产物中心主任）实验室鉴定 (UA)) 并由 PI Dr. Rajesh Khanna (UA) 表征为对 CIPN 中的 Cav3.2 具有选择性和抗药性。 在这项工作中，我们与 Regulonix, LLC 合作，对选定的 Cav3.2 目标化合物进行表征 及其类似物的体外和体内功效测定以及早期 ADME 和 PK 优化工作。 这里提出的第一步是为 CIPN 开发非阿片类药物疼痛治疗方法，同时也能遏制阿片类药物滥用 我们预计紫杉醇引起的慢性疼痛会成功转化为其他慢性疼痛。 类型也是如此，但 CIPN 重点关注早期概念验证，其具体目标是：(1) BA 类似物的设计和合成（L. Gunatilaka 博士）以及 Cav3.2 特异性和生物物理的阐明 选择 BA 类似物的特性，以获得机械和安全信息并记录独特的途径 神经元功能；(2) 分析 BA 类似物的体外细胞毒性、早期 ADME 和 药代动力学特性，以及筛选对 GPCR、离子通道和已知替代方案的脱靶效应 疼痛靶标，包括阿片受体；以及 (3) 描述目标 2 中用于临床前的最佳两种模拟 BA 使用神经性疼痛模型（紫杉醇）进行的研究提供有关口服功效、安全性和阿片类药物的信息 完成后，我们期望获得经过验证的 BA 类似物和几种有价值的备用化合物。