Development of selective Cav3 channel blockers for treatment of 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，目前的治疗往往难以治愈。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基于调节t型Ca2+通道。t型Ca2+通道在疼痛信号传导中起关键作用。Cav3通道家族至少参与了疼痛通路的两个关键阶段：第一，在背根神经节（DRG），第二，在丘脑疼痛传递。慢性神经收缩损伤和糖尿病性神经病变都会引起大鼠DRG神经元中其中一个通道（Cav3.2）的上调。相反，基因敲除、反义敲除或Cav3.2亚型沉默对大鼠或小鼠的神经性和炎症性疼痛均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优秀药物靶点。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hit化合物。效果最好的药物ML218可以减轻大鼠神经损伤引起的慢性疼痛、链脲佐菌素引起的糖尿病性神经病变和利血平引起的慢性疼痛。因此，我们选择ML218作为我们提出的SBIR快速通道项目中化学优化的起始化合物，用于我们的镇痛药物发现项目。我们将从ML218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（比ML218的效力和选择性更高）的前10个修饰导联。II期结束的里程碑是产生一种候选治疗药物，产生足够的体内疗效数据，中试安全性药理学和非nglp毒理学，这将有助于我们在SBIR II期竞争更新中做出IND支持研究的明智决定。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性地抑制Cav3通道来治疗慢性神经性疼痛。

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.