Development of selective Cav3 channel blockers for treatment of neuropathic pain

描述(申请人提供)：数百万美国人患有慢性神经性疼痛，这种疼痛通常对目前的治疗方法难以奏效。为了寻找解决这一慢性、无法治愈的疼痛的方法，我们打算开发一种基于T型钙通道调节的新的止痛疗法。T型钙通道在疼痛信号转导中起关键作用。Cav3家族的通道至少参与了痛觉通路的两个关键阶段：第一个阶段在背根节(DRG)，第二个阶段在丘脑痛觉传递。慢性神经压迫损伤和糖尿病神经病变均可引起大鼠背根神经节神经元中上述通道之一(Cav3.2)的上调。相反，基因敲除、反义敲除或沉默Cav3.2亚型在大鼠或小鼠的神经性和炎症性疼痛中都能产生良好的明显疼痛缓解。简而言之，T型钙通道似乎是治疗神经病理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Vanderbilt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热门化合物。最好的药物ML218可以缓解因备用神经损伤、链脲佐菌素诱导的糖尿病神经病变和利血平诱导的大鼠慢性疼痛而引起的慢性疼痛。因此，在我们的止痛药物发现计划的SBIR快速通道项目中，我们选择ML218作为化学优化的起始化合物。我们将从一组ML218衍生物的结构-活性关系(SAR)研究开始。从第一阶段发展到第二阶段的里程碑是确定符合我们选择标准(比ML218更高的效力和选择性)的前10个修改后的引线。第二阶段结束的里程碑是产生一种治疗候选药物，产生足够的体内疗效、试点安全药理学和非GLP毒理学数据，这将帮助我们在SBIR第二阶段的竞争性更新中为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使能研究并提交IND申请，它将在吸引非政府支持和行业合作伙伴进行临床开发方面具有巨大的价值。我们的最终目标是开发一种新的治疗方法，通过选择性和状态依赖地抑制Cav3通道来治疗慢性神经病理性疼痛。

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.