Selective Kv7.2/3 activators for the treatment of neuropathic pain

项目摘要 慢性疼痛的成功治疗在许多患者中是不够的，并导致了 滥用和上瘾阿片类药物，这是美国持续存在的重大公共卫生危机 全世界。开发非成瘾性疼痛疗法可以帮助对抗阿片成瘾和 使患者受益，包括那些遭受神经病理性疼痛的患者，特别是糖尿病神经病理性患者 疼痛(DNP)。我们项目的目标是开发一种安全、有效、不会上瘾的小分子药物 这激活了KV7电压门控钾通道，以解决DNP中过度活跃的神经元活动。 第一个具体目标是发现有利于在DNP中改变的KV7亚型的KV7激活剂，并在 背根神经节，即Kv7.2/3亚型。通过迭代领先优化研究，对我们的 新的KV7激活剂系列，我们的目标是Kv7.2/3激活，选择性高于Kv7.4 通道和其他Kv7.2/3激活剂的另一个关闭靶点，GABAA受体。这种方法是 预计将减少使用早期无偏KV7激活剂时观察到的偏离目标的副作用 包括尿滞留(由Kv7.4介导)和嗜睡和头晕(由 增强GABAA受体功能)。该阶段还包括吸收的优化， 分布、新陈代谢、排泄和毒性特征及其体外相关性的建立 在神经病理性大鼠DNP模型中的活动对体内疗效的影响。第二种动物模型是L5/L6脊柱 神经收缩模型，也将被用来测试候选化合物概括为 其他形式的神经性疼痛。第二个具体目标将是进一步描述两到四个 通过评估包括细胞色素P450在内的其他药理性质的先进化合物 诱导/时间依赖性抑制和体外安全性/选择性面板。第三个目标是选择一个 啮齿动物和非啮齿动物非GLP毒理学和药代动力学研究候选人 物种。具体目标四和五包括完成准备调查所需的研究 新药(IND)申请。这些研究包括化学品制造控制活动，如 候选药物合成的配方研究和良好的生产实践 心血管和安全性药理学研究，以及28天良好实验室实践毒理学研究 两种动物。这种筛查模式旨在建立一个临床准备就绪、耐受性良好和 广泛有效的治疗神经性疼痛的产品。

Project Summary The successful management of chronic pain is inadequate in many patients and has contributed to the abuse of and addiction to opioids, a continuing major public health crisis in the United States and worldwide. The development of non-addictive pain therapeutics can help counter opioid addiction and benefit patients, including those who suffer from neuropathic pain, and in particular diabetic neuropathic pain (DNP). Our project’s goal is to develop a safe, efficacious and non-addictive small-molecule drug that activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP. The first specific aim is discover Kv7 activators that favor Kv7 isoforms altered in DNP and found in dorsal root ganglia, namely the Kv7.2/3 isoforms. Through iterative lead optimization studies on our novel series of Kv7 activators, we are targeting Kv7.2/3 activation with selectivity over both Kv7.4 channels and another off target of other Kv7.2/3 activators, GABAA receptors. This approach is expected to decrease off-target side effects observed with the use of earlier non-biased Kv7 activators including urinary retention (mediated by Kv7.4), and somnolence and dizziness (mediated by enhancement of GABAA receptor function). This phase also includes optimization of absorption, distribution, metabolism, excretion, and toxicity profiles and building correlations between in-vitro activities to in-vivo efficacies in a neuropathic rat DNP model. A second animal model, the L5/L6 spinal nerve constriction model, will also be used to test the ability of candidate compounds to generalize to other forms of neuropathic pain. The second specific aim will be to further characterize two to four advanced compounds by assessing additional pharmacological properties including CYP450 induction/time dependent inhibition and in-vitro safety/selectivity panels. The third aim is to select a candidate for study in non-GLP toxicology and pharmacokinetic studies in rodent and non-rodent species. Specific aims four and five involve completing the studies needed to prepare an Investigational New Drug (IND) application. These studies include Chemical Manufacturing Controls activities such as formulation studies and Good Manufacturing Practices synthesis of drug candidate followed by cardiovascular and safety pharmacology studies, and 28-day Good Lab Practices toxicology studies in two animal species. This screening paradigm is intended to establish a clinic-ready, well-tolerated and widely effective product to treat neuropathic pain.