Orally-Bioavailable Peroxynitrite Decomposition Catalyst Targeting Post-Surgical Pain

针对手术后疼痛的口服生物可利用过亚硝酸盐分解催化剂

• 批准号: 9409804
• 负责人: SCOTT L DAX
• 金额: $ 65.81万
• 依托单位: CERSCI THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409804
• 关键词: Absence of pain sensation; Acute Pain; Adverse effects; Affect; Afferent Neurons; Age; American; Ames Assay; Analgesics; Arachidonic Acids; Bioavailable; Biological Assay; Biological Availability; Canis familiaris; Capsaicin; Cardiac; Cardiovascular Physiology; Cause of Death; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinic; Clinical Data; Clinical Research; Clinical Trials; Comorbidity; Constipation; Country; Cyclooxygenase Inhibitors; Data; Depression and Suicide; Development; Diabetes Mellitus; Dose; Double-Blind Method; Enzymes; Fentanyl; Free Radicals; Gated Ion Channel; Goals; Health Care Costs; Health Personnel; Healthcare Systems; Heart Diseases; Human; Impairment; In Vitro; Industrialization; Investigational Drugs; Investigational New Drug Application; Ion Channel; Ion Channel Gating; Laparoscopic Cholecystectomy; Lead; Legal patent; Ligands; Malignant Neoplasms; Medicine; Metals; Micronucleus Tests; Minor; Modeling; Morphine; Movement; Mutation; Nausea; Nervous system structure; Nitrogen; Nociception; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Opioid Receptor; Oral; Overdose; Oxygen; Pain; Pain management; Patients; Pattern; Peripheral Nervous System; Peroxonitrite; Pharmaceutical Preparations; Pharmacology; Phase; Placebo Control; Population; Postoperative Pain; Probability; Procedures; Production; Productivity; Property; Protein Isoforms; Randomized; Rattus; Respiratory physiology; Risk; Rodent; Safety; Schedule; Science; Sedation procedure; Series; Signal Transduction; Site; Sleep; Societies; Structural Chromosomal Abnormality; Structure; Surgical incisions; Testing; Therapeutic; Toxic effect; Toxicogenetics; Toxicology; Treatment Cost; Ventilatory Depression; Work; X ray diffraction analysis; X-Ray Diffraction; active control; addiction; analog; arm; base; catalyst; cost; disorder prevention; dosage; efficacy trial; experience; healthy volunteer; in vivo; inflammatory pain; innovation; middle age; mouse model; novel; novel drug class; novel strategies; novel therapeutics; opioid use; painful neuropathy; pre-clinical; prescription opioid; prevent; public health relevance; response; small molecule; success; third molar extraction; voltage

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

项目概要/摘要： 疼痛是目前我国最普遍、最致残、最昂贵的健康问题，这一问题将 随着人口的老龄化，疼痛的社会影响（例如，治疗费用，工作损失， 生产力下降，与成瘾，抑郁和自杀的共病）超过了每年的总和 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， 阿片类药物是成瘾性的，并且需要增加剂量以获得给定水平的疼痛缓解。的困难 阿片类药物使用所造成的危害因成瘾和滥用的巨大可能性而被极大地放大。根据 根据美国疾病控制和预防中心的数据，每天约有78人死于药物过量。 与处方止痛药有关 阿片类药物的这些问题，以及它们在长期内的有限功效，突出了对新药物的需求。 止痛药该项目的科学目的是进行研究，以推进一种有前途的新疼痛 治疗（CT-044），属于一种新的化学型/药理学类别，进入首次人体研究。我们 创新是第一个非金属基PN分解催化剂的发现。过去十年 表明1）自由基有助于疼痛和2）它们与伤害性感觉神经元的相互作用 在周围神经系统中扰乱伤害性信号。 我们的目标是通过研究性新药将我们的先导分子CT-044推向临床 本提案中所述的研究。正如下面将详细描述的，我们已经积累了一个 令人印象深刻的临床前数据包在这个领先的资产显示，该化合物是非常有效的， 切口和炎性疼痛模型。此外，CT-044具有良好的口服处置性和清洁性。 毒理学特征在各种各样的测定中。这促使我们提出一项直接进入第二阶段的建议， 进行GLP毒理学研究，以便向FDA提交IND申请，将该资产转移到临床， 术后疼痛的试验 我们相信，根据我们的经验，CT-044“数据包”超过，数据 即使是制药公司提出的最严格的标准， 先进的止痛药上市大多数拟议的工作构成剂量递增，以确定 早期人体剂量范围，并根据GLP进行（基本重复）毒理学研究，最后， 根据GMP生产CT-044。总的来说，这是一个难得的机会，以推进一个新的治疗类 由于广泛的临床前“去风险”研究， 1