Orally-Bioavailable Peroxynitrite Decomposition Catalyst Targeting Post-Surgical Pain

项目摘要/摘要： 疼痛目前是我国最普遍、最致残、最昂贵的健康问题，这个问题将 随着我们的人口老龄化继续增长。疼痛的社会影响(例如，治疗成本、工作损失、 工作效率下降、上瘾、抑郁和自杀的共病)超过了年度总和 心脏病、糖尿病和癌症的成本。不幸的是，今天主要用于治疗疼痛的药物， 阿片类药物会上瘾，需要增加剂量才能达到一定程度的止痛效果。困难所在 阿片类药物的使用所造成的影响被极大地放大了成瘾和滥用的巨大潜力。根据 美国疾病控制和预防中心称，每天约有78人死于服药过量 与处方止痛药有关。 阿片类药物的这些问题，以及它们在较长时间内的有限效力，突出了新的 止痛药。这个项目的科学目的是进行研究，以推进一种有希望的新痛苦 治疗性(CT-044)，属于一种新的化学类型/药理学类别，进入人类研究的第一阶段。我们的 创新之处在于发现了第一个非金属基聚对苯二甲酸分解催化剂。在过去的十年里 证明了1)自由基与疼痛有关，2)自由基与伤害性感觉神经元的相互作用 在外周神经系统中扰动伤害性信号。 我们的目标是通过研究中的新药将我们的先导分子CT-044转移到临床上 使本提案中描述的研究成为可能。正如下面将详细描述的，我们已经积累了一个 关于这一铅资产的令人印象深刻的临床前数据包表明，该化合物在 切口性和炎症性疼痛模型。此外，CT-044具有良好的口腔配置和清洁 各种化验方法中的毒理学概况。这促使我们寻求直接到第二阶段的提案，以 进行GLP毒理学研究，以便向FDA提出IND申请，以便将这些资产转移到临床 手术后疼痛的试验。 我们认为，根据我们的经验，CT-044的数据包超过了 即使是药房提出的最严格的标准，也可以与那些成功地 先进的止痛药上市。拟议工作的大部分构成了剂量递增，以便设置 早期人类剂量范围，以及在GLP下进行(基本上重复的)毒理学研究，最后， 按GMP标准生产CT-044。总而言之，这是一个难得的机会，可以推动一个新的治疗课程 由于广泛的临床前‘去风险’研究，成功的可能性很高。 1

Project Summary / Abstract: Pain is currently the most prevalent, disabling, and costly health issue in our country, and this problem will continue to grow as our population ages. The societal impact of pain (e.g., treatment costs, work loss, decreased productivity, co-morbidities with addiction, depression and suicide) exceeds the annual combined costs of heart disease, diabetes, and cancer. Unfortunately, the drugs predominantly used to treat pain today, opioids, are addictive and require increasing dosages to obtain a given level of pain relief. The difficulties posed by opioid use are magnified tremendously by the strong potential for addiction and abuse. According to the Centers for Disease Control and Prevention, approximately 78 people die every day from overdoses related to prescription painkillers. These problems with opioids, and their limited efficacy over the longer term highlight the need for new pain medicines. The scientific purpose of this project is to conduct studies to advance a promising new pain therapeutic (CT-044), belonging to a novel chemotype / pharmacological class, into first-in-human studies. Our innovation is the discovery of the first non-metal based PN decomposition catalyst. The past decade has demonstrated that 1) free radicals contribute to pain and 2) their interactions with nociceptive sensory neurons in the peripheral nervous system perturb nociceptive signaling. Our goal is to move our lead molecule, CT-044 into the clinic through the investigational new drug enabling studies described in this proposal. As will be described in detail below, we have amassed an impressive preclinical data package on this lead asset showing that the compound is highly efficacious in incisional and inflammatory pain models. In addition, CT-044 has a favorable oral disposition and a clean toxicology profile in a broad variety of assays. This motivates us to pursue a direct-to-phase-II proposal to conduct GLP toxicology studies to enable an IND application to the FDA to move this asset toward the clinic for trials for post-surgical pain. We believe, based upon our experience, that the CT-044 ‘data package’ exceeds, and that the data favorably compares to, even the most rigorous criteria posed by pharma houses that have successfully advanced analgesics to market. The majority of the proposed work constitutes dose escalation in order to set early human dose ranges, and conducting (essentially repeating) toxicological studies under GLP, and lastly, manufacturing CT-044 under GMP. Collectively this is a rare opportunity to advance a novel therapeutic class into humans with a high probability for success due to extensive preclinical ‘de-risking’ studies. 1