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: 8779431
• 负责人: Xinmin Simon Xie
• 金额: $ 22.5万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779431
• 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; 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; Solutions; 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; constriction; counterscreen; density; drug candidate; drug discovery; gabapentin; in vivo; industry partner; inflammatory neuropathic pain; inflammatory pain; knockout gene; meetings; monoamine; mortality; nerve injury; neurotransmitter release; nociceptive response; novel; novel therapeutics; painful neuropathy; patch clamp; pregabalin; programs; public health relevance; response; scaffold; screening; 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，这通常是目前治疗难治的。在寻找解决这个问题的慢性，无法治疗的疼痛，我们打算开发一种新的镇痛疗法的基础上调制的T型钙离子通道。T型钙通道在疼痛信号传导中起着关键作用。Cav 3通道家族参与疼痛通路的至少两个关键阶段：首先，在背根神经节（DRG），再次在丘脑疼痛中继。慢性神经收缩损伤和糖尿病性神经病变均引起大鼠DRG神经元中这些通道之一（Cav3.2）的上调。相反，Cav3.2同种型的基因敲除、反义敲减或沉默在大鼠或小鼠的神经性疼痛和炎性疼痛中产生良好的明显疼痛缓解。简而言之，T型Ca 2通道似乎是治疗神经性疼痛的极好的药物靶标。在我们完成的T通道生物探针发现项目（NS 050771/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。最好的命中，ML 218，减轻慢性疼痛引起的备用神经损伤，链脲佐菌素诱导的糖尿病神经病变和利血平诱导的慢性疼痛大鼠。因此，我们选择ML 218作为我们提出的SBIR快速通道项目的化学优化的起始化合物，用于我们的止痛药物发现计划。我们将从ML 218衍生物的结构-活性关系（SAR）研究开始。从I期进展到II期的里程碑是确定符合我们选择标准的前10个改良电极导线（比ML 218更高的效价和选择性）。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、初步安全药理学和非GLP毒理学数据，这将有助于我们在SBIR II期的竞争性更新中对IND使能研究做出通过/不通过的知情决定。一旦我们准备好进行IND研究并提交IND申请，它将在吸引非政府支持和工业合作伙伴进行临床开发方面具有巨大价值。我们的最终目标是开发一种选择性和状态依赖性抑制Cav 3通道的新型治疗方法来治疗慢性神经病理性疼痛。