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，从未有过开发新型非阿片类药物的未满足的医疗需求。 慢性疼痛的治疗比今天更加紧迫。超过6500万美国成年人患有 慢性疼痛，导致每年近6350亿美元的医疗费用。尽管它们的功效有限， 阿片类药物具有成瘾、耐受性和运动表现受损的潜力，已成为 慢性疼痛管理，导致阿片类药物流行病肆虐整个美国的社区。 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， 药物发现平台，以开发钙蛋白酶-1的选择性抑制剂作为新型非阿片类药物治疗剂， 慢性疼痛在慢性神经病理性疼痛动物模型中的研究表明， 钙蛋白酶-1，其下调K+ Cl-协同转运蛋白活性，导致突触抑制减弱 和神经性疼痛。我们小组先前的工作也表明，药理学抑制和 钙蛋白酶-1基因敲除减轻镰状细胞小鼠慢性疼痛行为 疾病（SCD）。重要的是，钙蛋白酶-1抑制的镇痛作用不诱导耐受性副作用， 这表明钙蛋白酶-1抑制剂具有非成瘾性的潜力。通过应用我们创新的人工 智能（AI）驱动的药物发现平台筛选虚拟化学库，我们确定了四（4） 新型钙蛋白酶-1抑制剂，并验证了它们在生化测定中的功效。在此，我们建议 将我们最有效的命中化合物进展为钙蛋白酶-1选择性半胱氨酸蛋白酶的先导化合物 家族选择性、非阿片类和CNS渗透剂，在3种慢性疼痛中至少有1种中证实有效 测试的动物模型包括慢性镰状细胞病疼痛、慢性炎性疼痛和慢性炎症性疼痛。 神经性疼痛提出了三个目标，包括目标1：合成~100个我们最有效的类似物 命中化合物，并表征体外活性和选择性。成功标准：前20名细胞渗透性， 钙蛋白酶-1抑制剂，对钙蛋白酶-2具有中等选择性，对组织蛋白酶具有高度选择性， 半胱天冬酶-1，目标2：评估我们来自目标1的前20种钙蛋白酶-1抑制剂的ADME-Tox和PK特征。 成功标准：前2种CNS渗透选择性钙蛋白酶-1抑制剂，具有有利的体内PK特征，以及 目的3：确定我们的首选钙蛋白酶-1抑制剂在3种慢性疼痛中的疗效和PK/PD关系 动物模型成功：3例慢性疼痛中至少1例的机械性痛觉过敏至少减少40%。 疼痛动物模型测试。第一阶段的成功完成将产生一种新型的CNS渗透剂， 在至少1种慢性疼痛动物模型中证实了钙蛋白酶-1抑制剂的有效性。我们的整体产品 将是第一个口服，中枢神经系统作用，选择性钙蛋白酶-1抑制剂慢性疼痛。重要的是，我们的产品 将减少慢性疼痛患者的阿片类药物使用，并有助于遏制美国阿片类药物的流行。