Inhibition of CaVα-β interaction with orally available small organic molecules for chronic pain

抑制 CaVα-β 与口服小有机分子相互作用治疗慢性疼痛

• 批准号: 10267604
• 负责人: Rajesh Khanna
• 金额: $ 40万
• 依托单位: REGULONIX, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267604
• 关键词: Acute; Acute Pain; Address; Afferent Neurons; Affinity; American; Amitriptyline; Analgesics; Antidepressive Agents; Arizona; Axon; Baclofen; Bioavailable; Biological Assay; Calcium; Calcium Channel; Cancer Patient; Cell-Mediated Cytolysis; Cells; Chemistry; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Cognitive; Complement; Complex; Complication; Coupled; Development; Disclosure; Dose-Limiting; Drug Kinetics; Dysesthesias; Effectiveness; Elan brand of omega-conopeptide MVIIA; Esthesia; Feeling; Fiber; G-Protein-Coupled Receptors; Goals; Human; In Vitro; Ion Channel; Ions; Laboratories; Lead; Malignant Neoplasms; Mediator of activation protein; Medical; Methods; Modeling; Motivation; Muscle relaxants; Neuraxis; Neurons; Neuropathy; Norepinephrine; Numbness; Opioid; Opioid Receptor; Oral; Paclitaxel; Pain; Pain management; Paresthesia; Pathogenesis; Pathway interactions; Penetration; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Phosphotransferases; Platinum Compounds; Prevalence; Property; Quality of life; Quinazolines; Rattus; Reflex action; Regimen; Rodent; Rotarod Performance Test; Running; Safety; Seminal; Sensory; Series; Serious Adverse Event; Serotonin; Shock; Site; Specificity; Spinal Cord; Spinal Ganglia; Structure; Surgical incisions; Survival Rate; Technology; Testing; Therapeutic; Translating; Treatment Protocols; Universities; Validation; Vinca Alkaloids; Work; addiction; analog; base; behavioral study; biophysical properties; cancer pain; cancer survival; cancer therapy; chemotherapeutic agent; chemotherapy; chronic pain; chronic painful condition; clinically relevant; compliance behavior; design; drug discovery; duloxetine; effective therapy; gabapentin; improved; in vivo; inhibitor/antagonist; interest; invention; lead series; meetings; motor impairment; neuronal excitability; neurotoxic; neurotoxicity; neurotransmission; non-opioid analgesic; novel; novel therapeutics; opioid use; pain model; pain relief; painful neuropathy; pre-clinical; preclinical study; preclinical trial; protein protein interaction; reuptake; sensory stimulus; side effect; small molecule; somatosensory; success; taxane; venlafaxine; voltage; web site; ziconotide

ABSTRACT Revisions noted in blue font 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 (small fibers), 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. For example, the taxane paclitaxel (Taxol®) increases N-type (CaV2.2) 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. CaV2.2 channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Though CaV2.2 has been targeted clinically with Prialt® and Gabapentin, both drugs are encumbered with serious side effects. This proposal aims to develop potent, orally available, and selective CaV2.2 channel antagonists, building on the seminal discovery of a quinazoline CaV2.2 antagonist (IPPQ) developed in the laboratory of Dr. Rajesh Khanna (University of Arizona (UA)), as potential candidates for the management of CIPN. IPPQ represents a new class of compounds targeting CaV2.2 via a completely unique mechanism – that of targeting the CaVα-CaVβ interface. For this work, we have partnered with Regulonix, LLC for characterizing select CaV2.2-targeted compounds and their analogs in in vitro and in vivo efficacy assays as well as early ADME profiling. The work proposed here is the first step in developing non-opioid pain treatments for CIPN. 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 (Dr. Marcel Patek, Medicinal chemistry consultant, former Vice President of Chemistry at Icagen, Inc.) and synthesis (Dr. Wei Wang, Director of the Drug Discovery Center, UA or CROs) and optimization of drug-like lead series (IPPQ) and elucidation of channel specificity and biophysical properties of select IPPQ analogs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells; (2) Profile IPPQ analogs for their in vitro cellular cytotoxicity, physico-chemical, early ADME, and for off-target effects on GPCRs, kinases, ion channels and alternative known pain targets; (3) Characterize the best three IPPQ analogs from Aim 2 for preclinical studies using a phenotypic screen for motor impairment (rotarod assay) and then test the two best IPPQ analogs in an acute pain model (paw incision) and an aggressive clinically-relevant neuropathic pain model (paclitaxel) to provide information about oral efficacy; behavioral studies will be registered at a preclinical trials website prior to the start. An operant method of pain testing with rodents that complements reflexive methods by addressing cognitive and motivational processing will also be used. At the conclusion of our study, we expect to have a validated IPPQ analog and several worthy backup compounds.

蓝色字体指出的摘要修订 化学疗法诱导的周围神经病（CIPN）是常见（患病率30-70％），并可能剂量 - 许多癌症化学疗法药物治疗方案的限制副作用。在临床上，CIPN表现出疼痛 那就是燃烧，射击或像电震动一样。癌症患病率的增加与增加 化学疗法方案引起的癌症存活率正在将癌症的疼痛转化为大型，未得到的医学 问题。神经毒性化学治疗剂（例如，抗紫杉醇（如紫杉醇））可能会引起结构性 外周神经（小纤维）的损害，导致外周的异常体感处理 和/或中枢神经系统。背根神经节（DRG）感觉神经元以及脊柱中的神经元细胞 脐带是化学疗法引起的神经毒性的首选部位。发病机理很复杂，但 包括离子通道中的改变。例如，紫杉烷紫杉醇（taxol®）增加N型（CAV2.2） 大鼠背根神经节（DRG）神经元中的电压门控Ca2+电流；这些神经元负责 传达有害的感觉刺激，表明这些渠道是特定感觉的重要介体 与CIPN相关的异常。 CAV2.2通道是增加神经元令人兴奋的关键决定者 和神经传递执行持续的神经性疼痛。尽管Cav2.2已在临床上被针对 使用Priort®和Gabapentin，两种药物都充满了严重的副作用。该建议旨在发展 潜力，口服可用和选择性CAV2.2渠道拮抗剂，建立在第二个发现的基础上 喹啉唑啉CAV2.2拮抗剂（IPPQ）在亚利桑那大学的Rajesh Khanna博士实验室中开发 （UA）），作为CIPN管理的潜在候选人。 IPPQ代表新的化合物 通过完全独特的机制来靶向CAV2.2 - 靶向CAVα-CAVβ界面。对于这项工作， 我们已经与Regulonix，LLC合作，以表征精选的CAV2.2靶向化合物及其类似物 体外和体内效率以及早期分析。这里提出的工作是第一步 开发CIPN的非阿片类药物疼痛治疗。我们预计与紫杉醇引起的慢性疼痛取得成功 也可以转化为其他慢性疼痛类型，但是CIPN为早期概念验证提供了重点。 Regulonix的具体目的是：（1）设计（Marcel Patek博士，医学化学顾问，以前的VICE ICAGEN，Inc。化学总裁）和合成（UA毒品发现中心主任Wei Wang博士 或CRO）和类似药物的铅系列（IPPQ）的优化以及通道特异性和生物物理的阐明 精选的IPPQ类似物的属性以获取机械和安全信息并记录独特的 相关神经元细胞功能的途径； （2）IPPQ类似物的体外细胞细胞毒性， 物理化学，早期ADME，以及对GPCR，激酶，离子通道和替代性已知的靶向效果 疼痛目标； （3）表征AIM 2的最佳三个IPPQ类似物，用于临床前研究 运动障碍的屏幕（Rotarod分析），然后在急性疼痛模型中测试两个最佳的IPPQ类似物 （PAW切口）和与临床相关的积极的神经性疼痛模型（紫杉醇），以提供信息 关于口服效率；行为研究将在开始之前在临床前试验网站上进行注册。操作员 用啮齿动物进行疼痛测试方法，该方法通过解决认知和 也将使用动机处理。在我们的研究结束时，我们希望有一个经过验证的IPPQ 模拟和几种珍贵的备份化合物。