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

基本信息

  • 批准号:
    9907446
  • 负责人:
  • 金额:
    $ 22.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 在美国,有 1 亿人患有慢性疼痛,这比以下疾病的患病率总和还多 癌症、糖尿病和心脏病。慢性疼痛是美国长期残疾的首要原因。 更糟糕的是,大量使用阿片类药物来治疗慢性疼痛加剧了药物滥用和成瘾, 将阿片类止痛药置于 2016 年夺走 42,000 名美国人生命的严重危机的核心。 危机发生后,总统宣布进入公共卫生紧急状态,而州立法者和各个卫生系统 开始采取措施限制医生开出的阿片类药物的数量。虽然这些措施 近年来,阿片类药物处方量减少了 22%,这使美国人遭受 慢性疼痛,几乎没有有效的选择。迫切需要替代性疼痛治疗。 辣椒素是一种植物来源的香料和药物,被配制为局部软膏中的镇痛剂 和真皮贴片以缓解疼痛。通过靶向瞬时受体电位来实现治疗效果 vanilloid 1 (TRPV1),从而使传递疼痛信号的神经通路失活。尽管 许诺的药用潜力、固有的刺激性和疏水性严重限制了其有效性和 辣椒素作为镇痛药的应用。检验 TRPV1 的假设非常重要 辣椒素的活性可以与辣味和疏水性分开。以我们的核心专业知识为基础 Young BioPharma 致力于合成和改进作为候选药物的生物活性天然产物 通过开发安全有效、基于天然产品的疗法来应对阿片类药物危机 慢性疼痛。通过我们的药物化学努力,我们纠正了文献中错误的 SAR 结论 报告证实了这一假设并发现了一种新型化合物 YB-2,具有有效的体外 TRPV1 调节作用 活性、低刺激性和高水溶性。我们相信这个有前途的代理人是一个理想的候选人 进一步发展。而不是像辣椒素那样受到低浓度局部使用效率低下的限制 由于刺激性和疏水性,YB-2 可以在临床试验中以更高的剂量使用,通过更多 有效静脉注射和口服给药。因此,实现治疗终点会容易得多。与一个 YB-2 具有良好的治疗效果,作为潜在的改变游戏规则的镇痛药开辟了一个全新的范式 疗法,为数百万患者提供安全有效的替代疼痛治疗。 该提案的总体目标是开发新型 TRP 调节剂 YB-2,以对抗阿片类药物危机并治疗 慢性疼痛。为了在 12 个月内推进该疗法向 FDA 提交 IND 申请 我们的目标是合成 1 g YB-2,确认体外活性,通过静脉注射在三种疼痛动物模型中测试 YB-2。 和口服给药,并进行 DMPK 研究。如果 YB-2 能够证明,我们认为第一阶段成功 3 种动物模型中至少有 2 种具有体内功效,且无明显副作用。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Young Shen其他文献

Young Shen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Clinical Outcome Assessments for Acute Pain Therapeutics in Infants and young Children (COA APTIC)
婴幼儿急性疼痛治疗的临床结果评估 (COA APTIC)
  • 批准号:
    10778757
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
Selective actin remodeling of sensory neurons for acute pain management
感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理
  • 批准号:
    10603436
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
Clinical Outcome Assessments for Acute Pain Therapeutics in Infants and young Children (COA APTIC)
婴幼儿急性疼痛治疗的临床结果评估 (COA APTIC)
  • 批准号:
    10783106
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
Development of A Focused Ultrasound Device for Noninvasive, Peripheral Nerve Blockade to Manage Acute Pain
开发用于非侵入性周围神经阻断来治疗急性疼痛的聚焦超声装置
  • 批准号:
    10740796
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
Predicting Pediatric Sickle Cell Disease Acute Pain Using Mathematical Models Based on mHealth Data
使用基于移动健康数据的数学模型预测儿童镰状细胞病急性疼痛
  • 批准号:
    10599401
  • 财政年份:
    2022
  • 资助金额:
    $ 22.5万
  • 项目类别:
Non-Contingent Acute Pain Stress Drives Analgesic Protection in Rats.
非偶然急性疼痛应激驱动大鼠镇痛保护。
  • 批准号:
    575854-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
Prefrontal Cortex Hemodynamic Responses to Mindfulness Meditation and Acute Pain
前额皮质血流动力学对正念冥想和急性疼痛的反应
  • 批准号:
    467076
  • 财政年份:
    2021
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Studentship Programs
A Multimodal Approach for Monitoring Prolonged Acute Pain in Neonates
监测新生儿长期急性疼痛的多模式方法
  • 批准号:
    9979265
  • 财政年份:
    2020
  • 资助金额:
    $ 22.5万
  • 项目类别:
Endocannabinoid Metabolism in Acute Pain
急性疼痛中的内源性大麻素代谢
  • 批准号:
    10356880
  • 财政年份:
    2020
  • 资助金额:
    $ 22.5万
  • 项目类别:
A Multimodal Approach for Monitoring Prolonged Acute Pain in Neonates
监测新生儿长期急性疼痛的多模式方法
  • 批准号:
    10218273
  • 财政年份:
    2020
  • 资助金额:
    $ 22.5万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了