Development of selective Cav3 channel blockers for treatment of neuropathic pain

开发用于治疗神经性疼痛的选择性 Cav3 通道阻滞剂

• 批准号: 9143175
• 负责人: Xinmin Simon Xie
• 金额: $ 74.17万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143175
• 关键词: Adverse drug effect; Afferent Neurons; American; Analgesics; Anticonvulsants; Antidepressive Agents; Behavior; Biological; Cell Line; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; Chronic; Clinical; Collaborations; Comorbidity; Contract Services; Data; Depressed mood; Development; Diabetic Neuropathies; Drug Interactions; Drug Kinetics; Drug Targeting; Electroencephalography; Emotions; Esthesia; Exhibits; Family; Fluoxetine; Freund' s Adjuvant; Gene Silencing; Generations; Goals; Health; Human; Human body; In Vitro; Injury; Ion Channel; Ions; Laboratories; Lead; Legal patent; Mental Depression; Methods; Modeling; Modification; Moods; Mus; Nerve; Neurons; Nociception; Norepinephrine; Opioid; Pain; Pathologic; Pathway interactions; Persistent pain; Pharmaceutical Chemistry; Pharmacology; Phase; Physiological; Play; Production; Protein Isoforms; Quality of life; Quantitative Structure-Activity Relationship; Rattus; Recombinants; Refractory; Regulation; Reserpine; Rodent; Rodent Model; Role; Safety; Selection Criteria; Sensory; Serotonin; Signal Transduction; Sleep; Small Business Innovation Research Grant; Solubility; Spinal Ganglia; Staging; Streptozocin; Structure-Activity Relationship; Synapses; Thalamic structure; Therapeutic; Toxicology; Trazodone; Tricyclic Antidepressive Agents; United States National Institutes of Health; Up-Regulation; analog; base; candidate identification; cardiovascular risk factor; channel blockers; chronic neuropathic pain; chronic pain; comorbid depression; constriction; counterscreen; density; drug candidate; drug discovery; gabapentin; in vivo; industry partner; inflammatory neuropathic pain; inflammatory pain; knock-down; knockout gene; meetings; monoamine; mortality; nerve injury; neurotransmitter release; nociceptive response; novel; novel therapeutics; painful neuropathy; patch clamp; pregabalin; programs; response; scaffold; screening; spared nerve; success; thalamic pain; voltage

DESCRIPTION (provided by applicant): Millions of Americans suffer from chronic neuropathic pain, which is often refractory to current treatment. In search of a solution to this problem of chronic, untreatable pain, we intend to develop a new analgesic therapy based on modulation of the T-type Ca2+ channel. T-type Ca2+ channels play key roles in pain signaling. The Cav3 family of channels is involved in at least two key stages of pain pathways: first, at the dorsal root ganglion (DRG) and again at the thalamic pain relay. Both chronic nerve constriction injury and diabetic neuropathy cause upregulation of one of these channels (Cav3.2) in the DRG neurons of rats. Conversely, gene knockout, antisense knockdown, or silencing of the Cav3.2 isoform produces good apparent pain relief in both neuropathic and inflammatory pain in rats or mice. In short, the T-type Ca2 channels appear to be excellent drug targets for treating neuropathic pain. In our completed T-channel biologic probe discovery project (NS050771/Xie), through collaboration with the Vanderbilt Screening/Chemistry Center, we discovered four hit compounds from two different novel chemical scaffolds. The best hit, ML218, mitigates chronic pain induced by spared nerve injury, streptozotocin-induced diabetic neuropathy and reserpine-induced chronic pain in rats. We have therefore selected ML218 as the starting compound for chemical optimization in our proposed SBIR Fast-Track project for our pain-relief drug discovery program. We will start with structure-activity relationship (SAR) studies on a focus set of ML218 derivatives. The milestone for advancement from Phase I to Phase II is identification of the top 10 modified leads that meet our selection criteria (higher potency and selectivity than ML218). The milestone for the end of Phase II is the production of a therapeutic candidate, generation of sufficient data of in vivo efficacy, pilot safety pharmacology, and nonGLP toxicology which will help us to make a go/no-go informed decision for IND- enabling studies in a Competing Renewal of SBIR Phase II. Once we are ready to conduct IND-enabling studies and file an IND application, it will be enormously valuable in attracting non-government support and industrial partners for clinical development. Our ultimate goal is to develop a novel therapeutic with selective and state-dependent inhibition of the Cav3 channel to treat chronic neuropathic pain.

描述（由申请人提供）：数以百万计的美国人患有慢性神经性疼痛，目前的治疗通常难以治愈。为了寻找解决慢性、无法治疗的疼痛问题的方法，我们打算开发一种基于 T 型 Ca2+ 通道调节的新镇痛疗法。 T 型 Ca2+ 通道在疼痛信号传导中发挥关键作用。 Cav3 通道家族至少参与疼痛通路的两个关键阶段：首先是背根神经节 (DRG)，其次是丘脑疼痛中继。慢性神经收缩损伤和糖尿病神经病变都会导致大鼠 DRG 神经元中这些通道之一 (Cav3.2) 的上调。相反，Cav3.2亚型的基因敲除、反义敲低或沉默对大鼠或小鼠的神经性疼痛和炎性疼痛产生良好的明显疼痛缓解。简而言之，T 型 Ca2 通道似乎是治疗神经性疼痛的极佳药物靶点。在我们完成的T通道生物探针发现项目（NS050771/Xie）中，通过与范德比尔特筛选/化学中心的合作，我们从两种不同的新型化学支架中发现了四种命中化合物。最畅销的药物 ML218 可减轻大鼠因幸存的神经损伤、链脲佐菌素引起的糖尿病神经病变和利血平引起的慢性疼痛。因此，我们选择 ML218 作为我们为我们的止痛药物发现计划提出的 SBIR 快速通道项目中化学优化的起始化合物。我们将从一组重点 ML218 衍生物的构效关系 (SAR) 研究开始。从第一阶段进展到第二阶段的里程碑是确定了符合我们选择标准的前 10 个修饰先导化合物（比 ML218 具有更高的效力和选择性）。 II 期结束的里程碑是生产候选治疗药物、生成足够的体内疗效数据、试验安全药理学和非 GLP 毒理学数据，这将帮助我们为 IND 做出是否继续的明智决定SBIR 第二阶段竞争更新的研究。一旦我们准备好进行 IND 支持研究并提交 IND 申请，这对于吸引非政府支持和工业合作伙伴进行临床开发将具有巨大价值。我们的最终目标是开发一种新型疗法，通过选择性和状态依赖性抑制 Cav3 通道来治疗慢性神经性疼痛。