Discovery of non-addictive KOR antagonists for migraine prophylaxis

发现用于预防偏头痛的非成瘾性 KOR 拮抗剂

基本信息

批准号：
9325694
负责人：
Lori Jean Van Orden
金额：
$ 123.7万
依托单位：
BLACKTHORN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325694
关键词：
Acute Adult Adverse effects Affect Amination Amines Amygdaloid structure Analgesic Overuse Headaches Animal Model Anti-Inflammatory Agents Anti-inflammatory Auras Behavior Biological Availability Blood Brain Brain region Categories Cell Membrane Permeability Cephalic Cerebrospinal Fluid Characteristics Chemicals Chronic Daily Headaches Classic Migraine Clinical Common Migraine Corticotropin-Releasing Hormone Cytochrome P450 Data Development Disease Dose Drug Kinetics Dynorphins Epidemic Evaluation Exposure to Foundations Frequencies Fright Functional disorder Goals Half-Life Headache Hour Human Hypersensitivity In Vitro Individual Infusion procedures Injury International Laboratories Lead Light Link Medical Metabolic Microinjections Migraine Modeling Mood Disorders Nausea and Vomiting Nociception Nociceptors Opioid Opioid Receptor Oral Pain Pathway interactions Patients Penetration Peptides Pharmaceutical Preparations Phase Physiological Population Pre-Clinical Model Preparation Prevention Preventive Property Prophylactic treatment Quality of life Rattus Reporting Rest Safety Sensory Thresholds Series Serum Severities Societies Spreading Cortical Depression Stimulus Stress Sumatriptan Symptoms System Tactile Testing Therapeutic Throbbing Headaches Tissues Toxicity Tests United States allodynia analog biological adaptation to stress central sensitization cutaneous allodynia dynorphin receptor in vitro Assay in vivo iterative design kappa opioid receptors nervous system disorder new therapeutic target norbinaltorphimine novel piperidine pre-clinical prevent programs prophylactic prototype psychologic public health relevance receptor response scaffold sound triptans

项目摘要

DESCRIPTION (provided by applicant): Migraine is the world's most common neurological disorder. This condition is characterized by a number of phases including a prodrome, the headache phase and a post-drome. In the headache phase, disabling cephalic pain occurs that is typically unilateral and persists for 4-72 hours. The migraine attack is also often associated with nausea, vomiting and hypersensitivity to a variety of external stimuli including light and sound. The International Headache Society distinguishes migraine without aura (MO) and migraine with aura (MA). The pathophysiology of migraine is not well understood but ultimately, migraine is believed to arise from a state of altered cortical excitability (dysexcitability) capabe of activating the trigeminovascular system in genetically susceptible individuals. One of the most commonly noted clinical triggers of migraine is stress. How stress may trigger migraine is unknown. Recent evidence suggests that stress activates the dynorphin/KOR system to produce multiple CNS effects. Our preliminary data suggest that stress can induce features that are consistent with clinical observations of migraine in a novel animal model of medication overuse headache (MOH) induced by a period of exposure to triptan drugs. In this proposal, we plan to discover a brain penetrant kappa opioid receptor (KOR) antagonist that can be developed for the prophylactic treatment of migraine. We will synthesize and optimize compounds from a preliminary scaffold, characterize them in vitro for their receptor selectivity, and evaluate them for harmacodynamics (PD), pharmacokinetic (PK), metabolic, side-effect and safety profiles in vivo. The first specific aim will synthesize and perform in vitro assays of novel 4-amine-N-(quinolyn-2- yl)piperidines. The second specific aim will assess the DMPK characteristics of these novel compounds. Aim 3 will characterize CYM51317, a prototype KOR antagonist, in migraine prevention in our rat MOH model and screen novel KOR antagonists for migraine prophylaxis to identify new molecules that have drug-like profiles that will enable IND-filing. These studies will allow identification of a candidate molecule that can be pursued for human evaluation.

描述（由申请人提供）：偏头痛是世界上最常见的神经系统疾病，其特征在于多个阶段，包括前驱症状、头痛阶段和后症状阶段。在头痛阶段，通常会出现致残性头侧疼痛。单侧且持续 4-72 小时的偏头痛发作通常还与恶心、呕吐和对各种外部刺激（包括光和声音）过敏有关。头痛协会区分无先兆偏头痛 (MO) 和有先兆偏头痛 (MA)。偏头痛的病理生理学尚不清楚，但最终，偏头痛被认为是由基因上激活三叉血管系统的皮质兴奋性（兴奋性障碍）状态引起的。偏头痛最常见的临床诱因之一是压力如何引发偏头痛，但最近的证据表明压力会引发偏头痛。我们的初步数据表明，压力可以诱发与在一段时间内接触曲坦类药物引起的药物过度使用性头痛 (MOH) 动物模型中的偏头痛临床观察结果一致的特征。根据该提案，我们计划发现一种可用于预防性治疗偏头痛的脑渗透性 kappa 阿片受体 (KOR) 拮抗剂。我们将从初步支架中合成和优化化合物，并在体外对其受体进行表征。第一个具体目标是合成新型 4-amine-N-(quinolyn-2) 并进行体外测定。第二个具体目标将评估这些新型化合物的 DMPK 特性，目标 3 将表征 CYM51317（一种原型 KOR 拮抗剂）在我们的大鼠 MOH 模型中的偏头痛预防作用。筛选用于预防偏头痛的新型 KOR 拮抗剂，以确定具有类似药物特征的新分子，从而能够进行 IND 申请。这些研究将能够识别可用于人体评估的候选分子。