Long acting and peripherally restricted kappa-opioid receptor agonists for acute migraine treatment

用于治疗急性偏头痛的长效外周限制型κ阿片受体激动剂

• 批准号: 10324497
• 负责人: Pierre Riviere
• 金额: $ 49.93万
• 依托单位: PEPTIDE LOGIC, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324497
• 关键词: Acute; Affect; Aftercare; Albumins; Amino Acids; Animal Model; Binding; Biological Availability; Calcitonin Gene-Related Peptide; Canis familiaris; Chemicals; Chronic Kidney Failure; Data; Development; Dose; Drug Kinetics; Dura Mater; Exhibits; Fatty Acids; Female; Formulation; Freedom; Generations; Goals; Half-Life; Hour; Human; Inflammation Mediators; Inpatients; Intravenous; Investigational New Drug Application; Kidney; Lead; Medical; Migraine; Modality; Molecular Weight; Monoclonal Antibodies; Mus; Nociception; Non-Steroidal Anti-Inflammatory Agents; Opioid agonist; Oral; Outpatients; Pain; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Preventive treatment; Pruritus; Quality of life; Renal function; Series; Serum Albumin; Small Business Innovation Research Grant; Solubility; Tablets; Technology; Transgenic Mice; Vertebral column; absorption; acute care; base; clinical candidate; design; follow-up; improved; innovation; kappa opioid receptors; lead optimization; male; mouse model; novel; pharmacophore; prevent; programs; prototype; public health relevance; receptor; screening; standard of care; success; triptans

ABSTRACT: Migraine is a highly prevalent and disabling illness affecting about 47 million people in the US.1 First-line therapies consist of acute treatments such as non-steroidal anti-inflammatory drugs (NSAIDS), triptans, ditans or gepants.2 Unfortunately, acute therapies are often poorly effective in many patients. Only about 20-30% of patients achieve freedom of pain at 2 hours post treatment with any of these drug classes.3-11 Non-responders to acute therapies with frequent episodic migraine are potential candidates for preventive treatments,2 including recently approved monoclonal antibodies (mAbs) for calcitonin gene-related peptide (CGRP) and its receptor (GGRPR).12-16 CGRP and CGRPR mAbs reduce the number of migraine days per month by 50% in 40-60% of patients,12-16 thus achieving only partial relief in responders and leaving a large group of non-responders without improvement. Overall, there are still large unmet medical needs in migraine, specifically for novel, and broadly effective acute treatments. We recently demonstrated that the peripheral kappa-opioid receptor (KOR) is a novel target for acute migraine treatment. We showed that the peripherally restricted KOR agonist difelikefalin reverses established migraine- like pain in mice resulting from direct activation of nociceptive afferents with a cocktail of inflammatory mediators (IM) applied to the dura mater. Our data suggest that peripherally restricted KOR agonists have the potential to be broadly effective and to achieve high efficacy for acute migraine treatment. The goal of this program is to develop long acting, peripherally restricted and hence non addictive, kappa-opioid receptor (KOR) agonists as novel, safe, and broadly effective acute migraine treatments. The proposed SBIR Phase I program will select a clinical candidate for development able to treat migraine headache and suitable for once-daily dosing, both as an intravenous (IV) formulation for use in inpatient settings or as an oral tablet for use in outpatient settings. Impact and

抽象的： 偏头痛是一种高度普遍且致残的疾病，影响了美国约4700万人。1一线 疗法包括急性治疗，例如非甾体类抗炎药（NSAID），triptans，ditans 2不幸的是，急性疗法在许多患者中通常效果不佳。只有约20-30％ 患者在治疗后2小时以这些药物类别获得疼痛自由。3-11无反应者 经常发作性偏头痛的急性疗法是预防治疗的潜在候选者，其中2包括 最近批准的降钙素基因相关肽（CGRP）及其受体的单克隆抗体（MAB） （GGRPR）.12-16 CGRP和CGRPR mAB在40-60％的40-60％中，每月偏头痛的数量减少了50％ 患者，12-16因此只能在反应者中得到部分缓解，并留下一大批非反应者 改进。总体而言，偏头痛中仍然有很大的未满足医疗需求，特别是针对小说的 有效的急性治疗。 我们最近证明了外围Kappa-阿片受体（KOR）是急性偏头痛的新目标 治疗。我们表明，受外围限制的Kor激动剂Difelikefalin逆转已建立的偏头痛 - 就像由炎症介质的鸡尾酒直接激活伤害性传入而导致的小鼠疼痛 （IM）应用于硬脑膜。我们的数据表明，受外围限制的Kor激动剂有可能 在急性偏头痛治疗方面具有广泛有效的效果。 该计划的目的是发展长期行动，外围限制，因此不成瘾，Kappa-Apoider 受体（Kor）激动剂是新颖，安全且广泛有效的急性偏头痛治疗。拟议的Sbir 第一阶段计划将选择一个能够治疗偏头痛的临床候选人，适合 每天一次的剂量，既可以作为静脉内（IV）用于住院设置或用作口服片剂的配方 在门诊设置中。 影响和