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

摘要 在美国有1亿人患有慢性疼痛，这超过了美国慢性疼痛患病率的总和 癌症、糖尿病和心脏病。在美国，慢性疼痛是导致长期残疾的头号原因。至 更糟糕的是，大量使用阿片类药物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一场肆虐的危机的核心，这场危机在2016年夺走了4.2万美国人的生命。为了遏制阿片类药物 危机，总统宣布进入公共卫生紧急状态，而州议员和各种卫生系统 开始制定措施，限制医生开出的阿片类药物的数量。尽管这些措施 与近年来阿片类药物处方减少22%不谋而合，这让美国人遭受 慢性疼痛，几乎没有有效的选择。有一个重大的和迫切的替代疼痛治疗的需要。 辣椒素是一种植物衍生的香料和药物，已被配方为局部软膏中的止痛剂。 和真皮贴片来缓解疼痛。治疗效果是通过靶向瞬时受体电位来实现的。 香草素1(TRPV1)，从而使传递疼痛信号的神经通路失活。尽管 药用潜力大，固有的刺激性和疏水性严重制约了其疗效和安全性。 辣椒素在镇痛药中的应用。检验TRPV1的假设是非常重要的 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 作为候选药物，Young BioPharma致力于合成和改进生物活性天然产物 通过开发安全有效的、以天然产品为基础的疗法来对抗阿片类药物危机 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 报道证实了这一假说，并发现了一种新的化合物YB-2，在体外具有强大的TRPV1调节作用 活性、低刺激性和高水溶度。我们相信这位有前途的代理人是理想的候选人 进一步发展。而不是像辣椒素那样在低浓度时被低效局部使用所限制 由于具有刺激性和疏水性，YB-2可以通过更多的临床试验以更高的剂量使用 有效静脉注射。和口服给药。因此，实现治疗终点将容易得多。使用一个 良好的治疗方案，YB-2开辟了一种全新的范式，成为潜在的改变游戏规则的止痛药 治疗，为数百万患者提供安全有效的替代疼痛治疗。 这项建议的总体目标是开发新型色氨酸调节剂YB-2，以对抗阿片类药物危象和治疗 慢性疼痛。为了推动这种疗法在12个月内与FDA一起应用于IND 我们的目标是合成1g的YB-2，确认其体外活性，并通过静脉注射在三种疼痛动物模型上测试YB-2。 和口服给药，并进行DMPK研究。如果YB-2能够证明，我们认为第一阶段是成功的 在3个动物模型中至少有2个在体内有效，没有明显的副作用。

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.