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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

基本信息

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
项目类别：
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

项目摘要

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

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