A novel TRP modulator YB-2 to fight opioid crisis and treat chronic pain

一种新型 TRP 调节剂 YB-2，可对抗阿片类药物危机并治疗慢性疼痛

• 批准号: 9907446
• 负责人: Young Shen
• 金额: $ 22.5万
• 依托单位: YOUNG BIOPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907446
• 关键词: Abdominal Pain; Acute; Acute Pain; Adult; American; Americas; Analgesics; Animal Model; Antineoplastic Agents; Area; Biological; Biological Assay; Capsaicin; Child; Clinical; Clinical Trials; Dermal; Development; Diabetes Mellitus; Diagnosis; Diarrhea; Dose; Drug Addiction; Drug abuse; Effectiveness; Erythema; Exhibits; Formalin; Funding; Health system; Heart; Heart Diseases; Hydrophobicity; In Vitro; Ingestion; Intravenous; Literature; Malignant Neoplasms; Measures; Mechanics; Medicine; Methodology; Nature; Nausea and Vomiting; Negligence; Neurologic; Ointments; Opioid; Opioid Analgesics; Oral; Oral Administration; Pain; Pain Research; Pain Threshold; Pain management; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plants; Preclinical Testing; Prevalence; Procedures; Public Health; Rage; Reflex action; Reporting; Research; Route; Site; Solubility; Spices; Sting Injury; Structure; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Topical application; Vanilloid; Water; analog; aqueous; base; bioactive natural products; chronic pain; clinical application; commercialization; design; disability; drug candidate; experience; fighting; improved; in vitro activity; in vivo; in vivo Model; in vivo evaluation; interest; non-opioid analgesic; novel; opioid epidemic; opioid mortality; pain model; pain relief; pain signal; prescription opioid; programs; public health emergency; receptor; scale up; side effect

Abstract There are 100 million people living with chronic pain in the U.S., which is more than the combined prevalence of cancer, diabetes and heart disease. Chronic pain is the number one cause of long-term disability in the U.S.. To make matters worse, the prolific use of opioids to treat chronic pain has exacerbated drug abuse and addiction, placing opioid painkillers at the heart of a raging crisis that took 42,000 American lives in 2016. To curb the opioid crisis, the president declared a public-health emergency while state lawmakers and various health systems started putting measures in place to cap the number of opioids prescribed by doctors. Although these measures have coincided with 22% reductions in opioid prescriptions in recent years, this leaves Americans suffering from chronic pain with few if any effective option. There is a significant and urgent need of alternative pain treatment. Capsaicin is a plant-derived spice and medicine that has been formulated as an analgesic in topical ointments and dermal patches to relieve pain. The therapeutic effect is achieved by targeting the transient receptor potential vanilloid 1 (TRPV1), thereby inactivating neurological pathways that transmit pain signals. Despite the promissory medicinal potential, the inherent pungency and hydrophobicity severely restrict the effectiveness and application of capsaicin as an analgesic drug. It is of great importance to test the hypothesis that the TRPV1 activity of capsaicin can be separated from the pungency and hydrophobicity. Building on our core expertise in synthesizing and improving bioactive natural products as drug candidates, Young BioPharma is dedicated to fighting the opioid crisis by developing safe and efficacious, nature product-based therapies for the treatment of chronic pain. Through our medicinal chemistry effort, we rectified the wrong SAR conclusions from the literature reports, confirmed the hypothesis and discovered a novel compound YB-2 with potent in vitro TRPV1 modulatory activity, low pungency and high aqueous solubility. We believe this promising agent is an ideal candidate for further development. Instead of being confined by inefficient topical use at low concentration like capsaicin due to pungency and hydrophobicity, YB-2 can be employed at much higher dose in clinical trials through more effective i.v. and oral administrations. Thus, it will be much easier to achieve therapeutic endpoints. With a favorable therapeutic profile, YB-2 opens up a brand-new paradigm as a potential game-changing analgesic therapy, providing millions of patients with alternative safe and efficacious pain treatment. The overall objective of this proposal is to develop novel TRP modulator YB-2 to fight opioid crisis and treat chronic pain. In order to advance this therapeutic towards the IND application with the FDA, within 12 months we aim to synthesize 1 g of YB-2, confirm the in vitro activity, test YB-2 in three animal models of pain via i.v. and oral administrations, and conduct DMPK studies. We consider phase I successful if YB-2 can demonstrate in vivo efficacy in at least 2 of the 3 animal models without significant side effect.

抽象的 美国有1亿人患有慢性疼痛 癌症，糖尿病和心脏病。慢性疼痛是美国长期残疾的第一大原因。 更糟糕的是，多产阿片类药物来治疗慢性疼痛会加剧药物滥用和成瘾， 将阿片类止痛药置于2016年遭受42,000次美国生命的爆发危机的核心。遏制阿片类药物 危机，总统宣布公共卫生紧急情况，而州立法者和各种卫生系统 开始采取措施限制医生规定的阿片类药物数量。虽然这些措施 近年来，阿片类药物处方减少了22％，这使美国人患有 慢性疼痛，很少有有效的选择。急需替代疼痛治疗。 辣椒素是一种植物来源的香料和药物 和真皮斑块以减轻疼痛。通过靶向瞬态受体电位来实现治疗效果 Vanilloid 1（TRPV1），从而灭活了传递疼痛信号的神经系统途径。尽管有 期票的药物潜力，固有的辛发和疏水性严重限制了有效性和 辣椒素用作镇痛药。检验TRPV1的假设非常重要 辣椒素的活性可以与辛辣和疏水性分开。以我们的核心专业知识为基础 综合和改善生物活性天然产物作为候选药物，年轻的生物制药致力于 通过开发安全有效的基于自然产品的疗法来治疗阿片类药物危机 慢性疼痛。通过我们的药物化学工作，我们纠正了文献中错误的SAR结论 报告，证实了该假设，并发现了一种具有有效体外TRPV1调节的新型化合物YB-2 活性，低刺和高水溶性。我们认为，这种有前途的代理人是 进一步发展。而不是限制在低浓度（如辣椒素）的低浓度下使用的局部使用 对于刺激性和疏水性，可以通过更多 有效i.v.和口头管理。因此，实现治疗终点将容易得多。与 YB-2良好的治疗概况，为可能改变游戏规则的镇痛作用打开了一个全新的范式 治疗，为数百万患者提供替代性安全有效的疼痛治疗。 该提案的总体目的是开发新颖的TRP调节器YB-2来抗击阿片类药物危机并治疗 慢性疼痛。为了在12个月内推进与FDA的IND应用程序有关IND应用的治疗方法 我们的目标是合成1 g YB-2，确认体外活性，通过i.v的三种动物疼痛模型测试YB-2。 和口头管理，并进行DMPK研究。如果YB-2可以证明 在3种动物模型中，至少有2个没有明显的副作用。