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

用于治疗神经性疼痛的选择性 Kv7.2/3 激活剂

• 批准号: 10450301
• 负责人: Lynn Resnick
• 金额: $ 220.07万
• 依托单位: KNOPP BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450301
• 关键词: Address; Adult; Animal Model; Animals; Back; Biological Assay; Canis familiaris; Capital; Cardiac; Cardiovascular system; Characteristics; Chemicals; Clinic; Development; Dizziness; Dose; Drowsiness; Drug Kinetics; Effectiveness; Enzymes; Excretory function; Family; Formulation; Funding; Future; Goals; Health Personnel; Human; In Vitro; Investigational Drugs; Investigational New Drug Application; Ion Channel; Maximum Tolerated Dose; Mediating; Metabolism; Modeling; Monkeys; Neurons; Neuropathy; Opiate Addiction; Opioid; Oral; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Potassium Channel; Privatization; Program Development; Property; Protein Isoforms; Public Health; Rattus; Research; Risk; Rodent; Safety; Series; Smooth Muscle; Spinal Ganglia; Spinal nerve structure; Testing; Therapeutic; Time; Toxic effect; Toxicology; Triage; United States; Urinary Retention; Voltage-Gated Potassium Channel; absorption; addiction; chronic pain management; clinical development; constriction; design; diabetic; diabetic rat; drug candidate; drug metabolism; drug synthesis; genotoxicity; in vitro activity; in vivo; lead candidate; lead optimization; medication safety; novel; opioid misuse; pain model; painful neuropathy; phase 2 study; pre-clinical; prescription opioid; programs; receptor; receptor function; response; scale up; screening; side effect; small molecule

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.

项目摘要 慢性疼痛的成功管理在许多患者中是不充分的，并导致了慢性疼痛的发生。 阿片类药物滥用和成瘾是美国持续的重大公共卫生危机， 国际吧非成瘾性疼痛疗法的发展可以帮助对抗阿片类药物成瘾， 有益于患者，包括患有神经性疼痛，特别是糖尿病性神经性疼痛的患者， 疼痛（DNP）。我们项目的目标是开发一种安全、有效、不成瘾的小分子药物 激活Kv 7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Kv 7激活剂，其有利于在DNP中改变的Kv 7亚型，并在DNP中发现。 背根神经节，即Kv7.2/3亚型。通过对我们的迭代领先优化研究， 作为一种新的Kv 7激活剂系列，我们靶向Kv7.2/3激活，其选择性超过Kv7.4和Kv7.4。 通道和其他Kv7.2/3激活剂，GABAA受体的另一个脱靶。这种方法 预期减少使用早期非偏倚Kv 7激活剂观察到的脱靶副作用 包括尿潴留（由Kv7.4介导）、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、代谢、排泄和毒性特征以及体外之间建立相关性 在神经病大鼠DNP模型中，将活性与体内功效进行比较。第二种动物模型，L5/L 6脊柱 神经收缩模型，也将用于测试候选化合物的能力，以推广到 其他形式的神经性疼痛。第二个具体目标将是进一步表征两到四个 通过评估其他药理学特性（包括CYP 450） 诱导/时间依赖性抑制和体外安全性/选择性小组。第三个目标是选择一个 啮齿类和非啮齿类动物非GLP毒理学和药代动力学研究的候选人 物种具体目标四和五涉及完成编写研究性报告所需的研究。 新药（IND）申请。这些研究包括化学生产控制活动，例如 候选药物的制剂研究和药品生产质量管理规范合成， 心血管和安全药理学研究，以及28天药物非临床研究质量管理规范毒理学研究， 两种动物这种筛查模式旨在建立一种临床准备就绪、耐受性良好且 广泛有效的治疗神经性疼痛的产品。