Novel CEHC Derivatives for Neuroinflammation

在SBIR I期(SBIR I)授权下进行的实验研究，1 R43 AG023510，已经确定了一种潜在的治疗肌萎缩侧索硬化症(ALS)的化合物。安可制药公司(EncorePharma)持有该化合物的成分物质专利。该化合物的体外作用方式及其活性 在G93A-SOD1 ALS小鼠模型的初步研究中，表明它可能是第一个对ALS疾病进展产生整体影响的候选药物。这项SBIR第二阶段申请(SBIR II)寻求对该化合物进一步临床前开发的支持，以准备向FDA提交研究新药(IND)申请，从而允许启动该化合物的临床试验。本文件中定义的重要临床前开发工作 SBIR II是一种潜在的重要新药剂商业化的第一步。与俄克拉荷马医学研究基金会(OMRF)在SBIR I方面成功的科学/商业合作将在SBIR II中得到进一步培养。SBIR II的具体目标是：在使用明确定义的ALS啮齿动物模型选择活性对映体的同时，优化给药水平和给药途径；进行化学过程开发 根据《药品生产质量管理规范》(GMP)进行中小规模的化合物(药物)生产；进行适当的辅助毒理学和药理学研究(包括基因毒性和新陈代谢) 根据良好的实验室实践；在ALS啮齿动物模型中评估C-tau和其他适当的分子作为转化为临床环境的生物标志物的实用性。在临床前安全性和有效性呈阳性的情况下，将准备一份IND，向FDA提交申请，寻求孤儿药物指定。由于这种化合物可能对肌萎缩侧索硬化症的神经炎性成分以及亨廷顿、帕金森和阿尔茨海默氏症等许多神经疾病起作用，EncorePharma将酌情支持在与这些疾病相关的模型和系统中使用该化合物和/或其他相关化合物进行实验研究。对于一种几乎没有治疗选择的疾病，推进这一潜在治疗方法的必要性不可低估。总共有60,000到100,000人 据估计，全世界在任何时候都会感染肌萎缩侧索硬化症，这种疾病的发病率约为每10万人中有5至9人。仅治疗性HALS的市场潜力就在1亿至3亿美元之间。

Experimental studies conducted under an SBIR Phase I (SBIR I) Grant, 1 R43 AG023510, have identified a compound that is a potential treatment for Amyotrophic Lateral Sclerosis (ALS). Encore Pharmaceuticals, Inc. (EncorePharma ) holds a composition of matter patent for the compound. The compound's mode of action in in vitro testing and its activity in preliminary studies in the G93A-SOD1 mouse model of ALS, suggest it may be the first drug candidate to have an overall impact on ALS disease progression. This SBIR Phase II Application (SBIR II) seeks support to further preclinical development of the compound in preparation for submission of an Investigational New Drug (IND) Application to the FDA, allowing initiation of clinical trials with the compound. The important preclinical development work defined in this SBIR II is the first step in commercialization of a potentially important new pharmaceutical agent. The successful scientific/business collaborations with the Oklahoma Medical Research Foundation (OMRF) in SBIR I will be further cultivated in SBIR II. The SBIR II Specific Aims are: to optimize the dose level and route of administration in concert with selecting the active enantiomer using well-defined rodent models of ALS; to conduct chemical process development and small to intermediate scale manufacture of compound (drug substance) according to Good Manufacturing Practices (GMP); to conduct appropriate supporting toxicology and pharmacology studies (including gene toxicity and metabolism) according to Good Laboratory Practices; to evaluate in ALS rodent models the utility of C-tau and other molecules as appropriate, as a biomarker for translation into the clinical setting. With a positive preclinical safety and efficacy profile, an IND will be prepared, filed with FDA and Orphan Drug Designation sought. As the compound may exert an effect against the neuroinflammatory component of ALS and many neurological diseases such as Huntington's, Parkinson's and Alzheimer's, EncorePharma will support, as appropriate, experimental studies with the compound and/or other related compounds in models and systems relevant to these diseases. The need to move this potential therapeutic forward for a disease that has very few treatment alternatives cannot be understated. A total of 60,000 to 100,000 individuals are estimated to be affected with ALS worldwide at any given time, and the incidence of the disease is approximately five to nine persons per 100,000. The market potential for a therapeutic hi ALS alone is $100-300 million.