Protease-activated-receptor-2 antagonists for treatment of migraine pain

蛋白酶激活受体 2 拮抗剂治疗偏头痛

• 批准号: 10602826
• 负责人: GREGORY O DUSSOR
• 金额: $ 31.04万
• 依托单位: PARMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602826
• 关键词: Acute; Affect; Affinity; Age; Agonist; Analgesic Overuse Headaches; Analgesics; Animal Model; Animals; Antibodies; Behavior; Benchmarking; Biochemistry; Biological Assay; Biological Availability; Blocking Antibodies; Blood - brain barrier anatomy; Brain; Brain Stem; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Canis familiaris; Cardiovascular Diseases; Cells; Central Nervous System; Chemicals; Constipation; Development; Dizziness; Doctor of Philosophy; Drug Kinetics; Drug Targeting; Elastases; Environment; Enzymes; Face; Formulation; Foundations; G alpha q Protein; Goals; Health; Healthcare; High Prevalence; Immune; Inflammation; Inflammation Mediators; Injections; Lead; Ligands; MAPK3 gene; Maintenance; Membrane; Meninges; Metabolic; Migraine; Modeling; Monoclonal Antibodies; Nausea; Neurons; Neurotransmitters; Non-Steroidal Anti-Inflammatory Agents; Opiate Addiction; Opioid; Oral; PAR-2 Receptor; Pain; Paresthesia; Pathway interactions; Patients; Penetrance; Peptide Hydrolases; Peptides; Peripheral; Peripheral Nerves; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Play; Pre-Clinical Model; Process; Productivity; Property; Public Health; Rattus; Receptor Activation; Receptor Inhibition; Risk; Role; Serotonin; Serotonin Agonists; Signal Pathway; Signal Transduction; Site; Stress; Testing; Texas; Therapeutic; Time; Toxicology; Trypsin; Tryptamines; Tryptase; Universities; Vasoconstrictor Agents; Workplace; abuse liability; addiction liability; analog; antagonist; antinociception; beta-arrestin; blood-brain barrier crossing; cardiovascular risk factor; care burden; cell analyzer; combat; cost; effective therapy; executive function; high throughput screening; improved; in vivo; inhibitor; mast cell; mechanical allodynia; meetings; mid-career faculty; migraine treatment; mouse model; neurotransmission; neurotransmitter release; novel; overdose death; pain model; pain perception; pain reduction; pain signal; peptidomimetics; pre-clinical; prevent; protein activation; receptor; response; scaffold; screening; serotonin receptor; side effect; small molecule; small molecule inhibitor; standard of care; transmission process; triptans

PROJECT SUMMARY Migraine affects over 36 million people in the US, particularly those of working age (18-55 years), negatively impacting workplace productivity and presenting an enormous healthcare burden. For almost half of those who suffer from migraine, current treatments fail to provide relief and have limited ability to reverse pain once it has started. The most effective medications either require injection (CGRP antibodies) or are associated with increased cardiovascular risk (triptans). In addition, none of these provide complete relief to most patients. Migraine pain results from aberrant activation of specialized neurons that innervate the meninges, resulting in the release of neurotransmitters that cause local inflammation, and trigger a pain signal to central terminals in the brainstem. This signal is then carried to higher brain centers resulting in the perception of pain, and the continued presence of inflammatory mediators in the periphery perpetuate this painful signal. Protease-activated-receptor-2 (PAR2) is a membrane receptor that is activated by enzymes that are released from immune cells in the meninges, over the course of a migraine attack. Its activation contributes to migraine pain at multiple points: increasing the release of excitatory neurotransmitters; lowering the threshold for activation of pain transmitting neurons; and promoting the synthesis of additional inflammatory mediators. The main site of action of PAR2 is in the peripheral nerve terminals. This is in contrast to the targets of current migraine therapeutics that also play major roles in the central nervous system. We have identified two small molecule inhibitors of PAR2 that reduce migraine-like pain in animals. Significantly, these molecules act without crossing the blood brain barrier (BBB), even when administered after the onset of an attack. In this proposal, we aim to modify the chemical scaffold of our lead compound to improve its potential for oral delivery. We will use a high throughput screen to examine inhibition of receptor activation and downstream signaling pathways. Selected compounds will then be tested for favorable pharmacokinetics (e.g., stability, oral bioavailability, and low BBB penetrance) and pain-reduction in animal models of migraine. The overall goal is to identify a lead compound that can be delivered orally to move into IND-enabling studies for the treatment of migraine pain.

项目摘要 偏头痛在美国影响了超过3600万人，特别是那些工作年龄（18-55岁）的人， 影响工作场所的生产力并带来巨大的医疗负担。对于几乎一半的人来说， 患有偏头痛，目前的治疗方法无法提供缓解，而且一旦出现疼痛，逆转疼痛的能力也有限 开始了最有效的药物要么需要注射（CGRP抗体），要么与 增加心血管风险（曲坦类）。此外，这些都不能完全缓解大多数患者。 偏头痛是由支配脑膜的专门神经元异常激活引起的，导致 神经递质的释放，引起局部炎症，并触发疼痛信号到中枢终端， 脑干然后，该信号被传递到更高的大脑中心，导致对疼痛的感知， 外周中炎性介质的持续存在使这种疼痛信号永久存在。 蛋白酶激活受体2（PAR 2）是一种膜受体，由释放的酶激活 在偏头痛发作的过程中，脑膜中的免疫细胞。它的激活有助于偏头痛 多点疼痛：增加兴奋性神经递质的释放;降低激活阈值 疼痛传递神经元;和促进额外的炎症介质的合成。的主要场所 PAR 2的作用是在外周神经末梢。这与当前偏头痛的目标相反 在中枢神经系统中也起主要作用的治疗剂。我们发现了两种小分子 PAR 2抑制剂，可减轻动物的偏头痛样疼痛。值得注意的是，这些分子的行为没有交叉 血脑屏障（BBB），即使在发作后给药。在本建议中，我们的目标是 修改我们的先导化合物的化学支架，以提高其口服给药的潜力。我们将使用高 通量筛选以检查受体活化和下游信号传导途径的抑制。选择 然后测试化合物的有利药代动力学（例如，稳定性、口服生物利用度和低BBB 在偏头痛动物模型中的镇痛作用。总体目标是确定一种先导化合物 它可以通过口服给药进入IND治疗偏头痛的研究。