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

用蓝色字体标注的修订 化疗引起的周围神经病变（CIPN）是一种常见的（患病率30-70%）和潜在的剂量- 限制了许多癌症化疗药物治疗方案的副作用。临床上，CIPN表现为疼痛 燃烧、射击或类似电击。癌症发病率的增加， 由于化疗方案的癌症存活率正在将癌症疼痛转化为一个巨大的，未满足的医疗需求， 问题.神经毒性化疗剂（例如，紫杉醇等抗微管药物）可能会导致结构性 周围神经（小纤维）损伤，导致周围神经中的异常体感处理 和/或中枢神经系统。背根神经节（DRG）感觉神经元以及脊髓背角中的神经元细胞 脊髓是化疗引起神经毒性的优先发生部位。发病机制复杂， 包括离子通道的改变。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Ca 2+电流;这些神经元负责 传递有害的感觉刺激，表明这些通道是特定感觉的重要介质， 与CIPN相关的异常。CaV2.2通道是神经元兴奋性增加的关键决定因素 以及伴随持续性神经病理性疼痛的神经传递。尽管CaV2.2已被临床靶向 与Prialt®和加巴喷丁相比，这两种药物都有严重的副作用。该提案旨在发展 一种有效的，口服的，选择性的CaV2.2通道拮抗剂，建立在开创性的发现， Rajesh卡纳博士（亚利桑那大学）实验室开发的喹唑啉CaV2.2拮抗剂（IPPQ (UA))，作为CIPN管理层的潜在候选人。IPPQ代表了一类新的化合物 通过完全独特的机制靶向CaV 2.2-靶向CaVα-CaVβ界面。对于这项工作， 我们已经与Regulonix，LLC合作，对特定的CaV2.2靶向化合物及其类似物进行表征 在体外和体内功效测定以及早期ADME谱中。这里提出的工作是第一步， 为CIPN开发非阿片类药物疼痛治疗。我们预期成功对抗紫杉醇引起的慢性疼痛 也可以转化为其他慢性疼痛类型，但CIPN为早期概念验证提供了重点。 Regulonix的具体目标是：（1）设计（Marcel Patek博士，药物化学顾问，前Vice Icagen，Inc.的化学总裁）和合成（Dr. Wei Wang，Director of Drug Discovery Center，UA 或CRO）和药物样先导系列（IPPQ）的优化以及通道特异性和生物物理特性的阐明。 选择IPPQ类似物的性质，以获得机械和安全信息，并记录独特的 在相关神经元细胞中的功能通路;（2）分析IPPQ类似物的体外细胞毒性， 物理化学、早期ADME以及对GPCR、激酶、离子通道和已知替代药物的脱靶效应 疼痛靶点;（3）使用表型分析表征来自Aim 2的用于临床前研究的最佳三种IPPQ类似物， 筛选运动障碍（转棒试验），然后在急性疼痛模型中测试两种最佳IPPQ类似物 (paw切口）和侵袭性临床相关神经性疼痛模型（紫杉醇）以提供信息 关于口服疗效;行为研究将在开始前在临床前试验网站上注册。的操作性 一种啮齿动物疼痛测试方法，通过解决认知和 还将使用动机处理。在我们的研究结束时，我们希望有一个经过验证的IPPQ 模拟和几个有价值的备份化合物。

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.