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: 10487454
• 负责人: Pierre Riviere
• 金额: $ 19.94万
• 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/10487454
• 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; Persons; 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; migraine treatment; 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

摘要： 偏头痛是一种高度流行的致残性疾病，影响着美国约4700万人。 治疗包括急性治疗，如非甾体抗炎药（NSAIDS）、曲坦类、地坦类 2不幸的是，急性疗法在许多患者中通常效果不佳。只有大约20-30%的 患者在使用这些药物类别中的任何一种治疗后2小时达到疼痛的自由。3 -11无应答者 对频繁发作性偏头痛的急性治疗是预防性治疗的潜在候选者，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） 12 -16 CGRP和CGRPR mAb在40-60%的受试者中将每月偏头痛天数减少50%， 患者，12-16，因此仅在应答者中实现部分缓解，并留下一大群无应答者， 改进.总体而言，偏头痛仍有大量未满足的医疗需求，特别是对于新的，广泛的 有效的急性治疗。 我们最近发现外周κ-阿片受体（KOR）是急性偏头痛的一个新靶点 治疗我们发现，外周限制性KOR激动剂difelikefalin逆转了已建立的偏头痛， 如小鼠中的疼痛是由伤害性传入神经与炎性介质的混合物直接激活引起的 (IM)应用于硬脑膜。我们的数据表明，外周限制性KOR激动剂有可能 对急性偏头痛的治疗具有广泛的有效性和高的疗效。 该计划的目标是开发长效，外周限制，因此不会上瘾，kappa阿片类药物 受体（KOR）激动剂作为新型、安全和广泛有效的急性偏头痛治疗。拟议的SBIR I期项目将选择一种临床候选药物进行开发，该药物能够治疗偏头痛， 每日一次给药，作为静脉（IV）制剂用于住院患者或作为口服片剂用于 在门诊设置。 影响和