A NOVEL APPROACH FOR PAIN TREATMENT WITHOUT OPIOID LIABILITIES

一种没有阿片类药物副作用的疼痛治疗新方法

• 批准号: 9270527
• 负责人: Nurulain T Zaveri
• 金额: $ 73.6万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270527
• 关键词: Absence of pain sensation; Acute Pain; Adult; Adverse effects; Affect; African American; Agonist; American; Analgesics; Animal Model; Biological Assay; Biological Availability; Brain; Capsaicin; Child; Chronic; Clinical; Clinical Trials; Constipation; Data; Development; Disease; Dose; Drug Kinetics; Effectiveness; Evaluation; Family; Future; Hispanics; Human; Hyperalgesia; Hypoxia; In Vitro; Inflammatory; Ion Channel; Lead; Life; Ligands; Manuscripts; Metabolic; Modality; Modeling; Modification; Monkeys; Morphine; Mus; Narcotic Antagonists; National Institute of Neurological Disorders and Stroke; Nausea; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Pain; Pain Research; Pain management; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Productivity; Public Health; Quality of life; Research; Rewards; Rodent; Rodent Model; Safety; Sickle Cell Anemia; Solid; Spinal Cord; Symptoms; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; United States; Work; allodynia; base; chronic pain; cost; cytokine; delta opioid receptor; design; drug candidate; drug development; effective therapy; experience; improved; in vivo; inflammatory pain; mast cell; member; mouse model; mu opioid receptors; nociceptin; nonhuman primate; novel; novel strategies; painful neuropathy; patch clamp; phase 1 study; pre-clinical; preclinical development; preference; public health relevance; receptor; receptor binding; sickling; small molecule; standard of care; translational study

 DESCRIPTION (provided by applicant): Every year, about 100 million adult Americans experience some form of pain, a condition that costs the nation between $560 billion and $635 billion annually in lost productivity and treatment. The recently released `National Pain Strategy' developed by the NINDS's IPRCC, recognizes acute and chronic pain as a serious and costly public health issue, and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US. Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief. However, opioid analgesics (which are mainly mu opioid receptor (MOP) agonists) are controlled substances that have abuse potential and are riddled with other side effects such as constipation, nausea, and tolerance, which impede their long-term safety and effectiveness. There is clearly a need for new analgesics that provide opioid-like efficacies without the liabilities of opioid pain-killers. he nociceptin opioid receptor (NOP), the 4th member of the opioid receptor family, and its endogenous peptide ligand, nociceptin/orphanin FQ (N/OFQ) are emerging new targets for pain medications. The NOP receptor and N/OFQ are found throughout in pain-processing pathways in the brain and spinal cord, and modulate opioid function by blocking opioid reward and even tolerance. We and others have shown that the natural peptide N/OFQ and small-molecule NOP agonists and bifunctional' NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain, are non-rewarding and do not develop tolerance. These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid-related liabilities. In our Phase I project, we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell disease'(SCD), which develops spontaneous hyperalgesia similar to the condition in sickle patients. SCD is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance, remain a sub-optimal approach to treat SCD pain, particularly when needed on a continued basis. Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD. Our Phase I studies showed that the NOP agonist-mu low efficacy agonist AT-200 showed significant antinociceptive efficacy in sickle mice, more potent and longer-lasting than high-dose morphine. AT-200 also showed a sustained analgesic effect, without tolerance development. These promising data that NOP agonists and/or NOP-mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain. In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP-targeted `preclinical lead candidates', which are optimized for their drug-like suitability and novelty, hav in vivo efficacy in pain models in rodents and nonhuman primates, and preliminary evaluation of toxicity, that are ready to be advanced into IND-enabling studies for development as pain medications.

 每年，大约有1亿成年美国人经历某种形式的疼痛，这种情况每年在生产力和治疗方面损失5600亿至6350亿美元。NINDS的IPRCC最近发布的“国家疼痛战略”承认急性和慢性疼痛是一个严重和昂贵的公共卫生问题，并阐明需要开发新的治疗方法来减轻美国的疼痛负担。阿片类镇痛药是疼痛治疗的支柱，通常是唯一能提供显著缓解的治疗选择。然而，阿片类镇痛药（主要是μ阿片受体（MOP）激动剂）是受管制的物质，具有滥用潜力，并充满了其他副作用，如便秘，恶心和耐受性，这阻碍了它们的长期安全性和有效性。显然需要提供类阿片样功效而没有类阿片止痛药的负担的新镇痛剂。阿片受体家族的第4个成员--痛敏肽阿片受体（nociceptin opioid receptor，NOP）及其内源性肽配体--痛敏肽/阿片肽FQ（nociceptin/nociceptin/OFQ，N/OFQ）是近年来出现的镇痛药物的新靶点。NOP受体和N/OFQ贯穿于大脑和脊髓的疼痛处理通路，并通过阻断阿片奖励甚至耐受来调节阿片功能。我们和其他人已经表明，天然肽N/OFQ和小分子NOP激动剂以及具有μ阿片样物质激动剂活性的双功能NOP激动剂对急性和慢性疼痛显示出有效的镇痛作用，是非回报的并且不产生耐受性。这些发现表明，NOP受体激动剂可能是一种有吸引力的方法，以获得有效的镇痛效果，而没有阿片类药物相关的负债。在我们的I期项目中，我们研究了NOP激动剂在“镰状细胞病”（SCD）转基因小鼠模型中的镇痛潜力，该模型产生与镰状细胞病患者相似的自发性痛觉过敏。SCD与严重疼痛相关，这仍然是治疗的主要挑战。阿片类药物是目前的标准治疗，但由于副作用和耐受性的发展，仍然是治疗SCD疼痛的次优方法，特别是在需要持续治疗时。开发不含阿片类药物的有效镇痛药将对疼痛治疗产生重大影响 在SCD。我们的I期研究表明，NOP激动剂-μ低效激动剂AT-200在镰状小鼠中显示出显著的抗伤害感受功效，比高剂量吗啡更有效且更持久。AT-200还显示出持续的镇痛作用，没有耐受性发展。这些有希望的数据表明，NOP激动剂和/或NOP-mu双功能激动剂是用于治疗慢性疼痛如镰状疼痛的有希望的镇痛剂。在第二阶段，我们 建议进行先导化合物优化和药物化学，以确定新型NOP靶向的“临床前先导化合物候选物”，这些药物针对其药物样适用性和新奇进行了优化，在啮齿动物和非人灵长类动物的疼痛模型中具有体内疗效，并进行了初步毒性评价，这些药物已准备好进入IND使能研究，以开发为止痛药。