Development of selective calpain-1 inhibitors for chronic pain

开发治疗慢性疼痛的选择性 calpain-1 抑制剂

• 批准号: 10078437
• 负责人: Jennifer O Nwankwo
• 金额: $ 54.64万
• 依托单位: 1910 GENETICS INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078437
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Analgesics; Animal Model; Artificial Intelligence; Attenuated; Binding; Binding Proteins; Biochemical; Biological Assay; Biological Availability; Biological Markers; Brain; CASP1 gene; Calpain; Caspase; Catalytic Domain; Cathepsin L; Cathepsins; Cells; Chemicals; Chronic; Chronic inflammatory pain; Clinical; Collaborations; Communities; Data; Data Set; Development; Disease; Dose; Enzymes; Family; Genetic; Health Care Costs; Hepatocyte; Homeostasis; Human; Hyperalgesia; Inflammation; Inflammatory; Knock-out; Lead; Libraries; Ligation; Liver; Malignant Neoplasms; Mechanics; Medical; Modeling; Mus; Neuraxis; Neuropathy; Opioid; Oral; Pain; Performance; Peripheral nerve injury; Permeability; Pharmacologic Substance; Pharmacology; Phase; Plasma Proteins; Rattus; Recording of previous events; Reporting; Research; Route; Sickle Cell Anemia; Small Business Innovation Research Grant; Small Interfering RNA; Solubility; Speed; Spinal Cord; Spinal nerve structure; Sulfonamides; Synapses; Testing; Texas; Training; United States; Universities; Work; Zymosan; addiction; analog; base; benzothiazole; blood-brain barrier permeabilization; bone; calpain inhibitor; chloride-cotransporter potassium; chronic neuropathic pain; chronic pain; chronic pain management; chronic pain patient; delta opioid receptor; diabetic; drug development; drug discovery; efficacy study; efficacy testing; improved; in vitro Assay; in vitro activity; in vivo; inhibitor/antagonist; innovation; lead optimization; m-calpain; motor impairment; mouse model; mu-calpain; nerve injury; non-opioid analgesic; novel; opioid epidemic; opioid use; pain behavior; pain model; pain reduction; pain sensitivity; painful neuropathy; peptidomimetics; pharmacokinetics and pharmacodynamics; protein expression; response; scaffold; screening; side effect; small molecule libraries; spared nerve; stem; success; synaptic inhibition; virtual; virtual library

PROJECT SUMMARY Never in the history of the United States has the unmet medical need to develop novel, non-opioid therapeutics for chronic pain been more urgent than it is today. More than 65 million US adults suffer from chronic pain, resulting in almost $635 billion in annual healthcare costs. Despite their limited efficacy, and potential for addiction, tolerance, and impaired motor performance, opioids have become a mainstay for chronic pain management, resulting in an opioid epidemic that is ravaging communities throughout the US. Thus, there is an urgent need to develop novel, non-opioid therapies for chronic pain management. This application addresses this unmet medical need by leveraging our novel artificial intelligence (AI)-driven drug discovery platform to develop selective inhibitors of calpain-1 as novel non-opioid therapeutics for chronic pain. Studies in chronic neuropathic pain animal models have shown that nerve injury overactivates calpain-1, which downregulates K+ Cl- cotransporter activity, resulting in diminished synaptic inhibition and neuropathic pain. Prior work by our group has also shown that both pharmacological inhibition and whole body genetic knockout of calpain-1 attenuates chronic pain behaviors in mouse models of sickle cell disease (SCD). Importantly, the analgesic effect of calpain-1 inhibition did not induce tolerance side effects, suggesting the potential for calpain-1 inhibitors to be non-addictive. By applying our innovative artificial intelligence (AI)-driven drug discovery platform to screen a virtual chemical library, we identified four (4) novel calpain-1 inhibitors, and validated them for efficacy in biochemical assays. Here, we propose to progress our most potent hit compound to a lead compound that is calpain-1 selective, cysteine protease family selective, non-opioid, and CNS penetrant with efficacy demonstrated in at least 1 of 3 chronic pain animal models tested, including chronic sickle cell disease pain, chronic inflammatory pain, and chronic neuropathic pain. Three aims are proposed, including Aim 1: Synthesize ~100 analogs of our most potent hit compound, and characterize in vitro activity and selectivity. Success criteria: Top 20 cell-permeable, calpain-1 inhibitors, moderately selective against calpain-2, and highly selective against cathepsins and caspase-1, Aim 2: Evaluate ADME-Tox and PK profile of our top 20 calpain-1 inhibitors from Aim 1. Success criteria: Top 2 CNS-penetrant selective calpain-1 inhibitors with favorable in vivo PK profile, and Aim 3: Determine the efficacy and PK/PD relationship of our top calpain-1 inhibitor in 3 chronic pain animal models. Success: at least 40% reduction in mechanical hyperalgesia in at least 1 of the 3 chronic pain animal models tested. Successful completion of this Phase I will yield a novel CNS-penetrant, selective calpain-1inhibitor with efficacy demonstrated in at least 1 chronic pain animal model. Our overall product would be the first, oral, CNS acting, selective calpain-1 inhibitor for chronic pain. Importantly, our product would reduce opioid usage in chronic pain patients, and help to stem the US opioid epidemic.

项目摘要 在美国历史上从来没有未满足的医学需求来发展新颖的非阿片类药物 慢性疼痛的治疗学比今天更加紧急。超过6500万美国成年人遭受 慢性疼痛，每年的医疗保健费用近6350亿美元。尽管功效有限，并且 成瘾，耐受性和运动性能受损的潜力，阿片类药物已成为中流tay的支柱 慢性疼痛管理，导致阿片类药物流行，该流行病正在整个美国破坏社区。 因此，迫切需要开发用于慢性疼痛管理的新型非阿片类药物疗法。这 应用程序通过利用我们的新型人工智能（AI）驱动来解决这种未满足的医疗需求 药物发现平台以开发钙蛋白-1的选择性抑制剂作为新型非阿片类药物治疗剂 慢性疼痛。慢性神经性疼痛动物模型的研究表明，神经损伤过度激活 Calpain-1下调K+ Cl-Cotransporter活性，导致突触抑制作用减少 和神经性疼痛。我们小组的先前工作还表明，药理学抑制和 Calpain-1的全身遗传敲除可减轻镰状细胞模型中的慢性疼痛行为 疾病（SCD）。重要的是，calpain-1抑制的镇痛作用不会引起耐受性副作用， 提出calpain-1抑制剂的潜力是非添加的。通过应用我们的创新人造 情报（AI）驱动的药物发现平台以筛选虚拟化学库，我们确定了四个（4） 新型的Calpain-1抑制剂，并验证了它们在生化测定中的功效。在这里，我们建议 进步我们最有效的命中化合物到铅1选择性，半胱氨酸蛋白酶的铅化合物 家庭选择性，非阿片类和中枢神经系统具有疗效，至少有3种慢性疼痛 测试的动物模型，包括慢性镰状细胞疾病疼痛，慢性炎症性疼痛和慢性 神经性疼痛。提出了三个目标，包括目标1：合成〜我们最有效的100个类似物 点击化合物，并表征体外活性和选择性。成功标准：前20个细胞渗透， CALPAIN-1抑制剂，对Calpain-2的适度选择性，对组织蛋白酶和高度选择性 CASPASE-1，AIM 2：从AIM 1中评估我们前20个Calpain-1抑制剂的ADME-TOX和PK谱。 成功标准：具有良好体内PK曲线的前2个CNS penert剂选择性Calpain-1抑制剂，并且 AIM 3：确定3个慢性疼痛中顶级钙蛋白-1抑制剂的功效和PK/PD关系 动物模型。成功：在3个慢性中，至少有1个降低了机械痛觉过敏的40％ 测试的疼痛动物模型。该阶段的成功完成I将产生一种新型的CNS-PENETRANT，选择性 至少1个慢性疼痛动物模型中证明了具有功效的Calpain-1抑制剂。我们的整体产品 对于慢性疼痛，将是第一个，口服CNS作用，选择性CALPAIN-1抑制剂。重要的是，我们的产品 会减少慢性疼痛患者的阿片类药物使用情况，并有助于阻止美国阿片类药物流行。