Novel CEHC Derivatives for Neuroinflammation

在SBIR I期（SBIR I）资助（1 R43 AG 023510）下进行的实验研究已经确定了一种潜在治疗肌萎缩侧索硬化症（ALS）的化合物。Encore Pharmaceuticals，Inc.（EncorePharma）持有该化合物的物质组合物专利。该化合物在体外试验中的作用方式及其活性 在ALS的G93 A-SOD 1小鼠模型的初步研究中，表明它可能是第一个对ALS疾病进展具有全面影响的候选药物。本SBIR II期申请（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提交研究性新药（IND）申请，从而启动该化合物的临床试验。本文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。SBIR I中与俄克拉荷马州医学研究基金会（OMRF）成功的科学/商业合作将在SBIR II中进一步培养。SBIR II的具体目的是：使用明确的ALS啮齿动物模型，优化剂量水平和给药途径，同时选择活性对映体;进行化学工艺开发 根据药品生产质量管理规范（GMP）进行小规模至中等规模的化合物（原料药）生产;进行适当的支持性毒理学和药理学研究（包括基因毒性和代谢） 根据药物非临床研究质量管理规范;在ALS啮齿动物模型中评价C-tau和其他分子（如适用）作为生物标志物转化为临床环境的效用。在临床前安全性和有效性方面具有积极意义的情况下，将准备IND，向FDA提交并寻求孤儿药指定。由于该化合物可能对ALS和许多神经系统疾病（如亨廷顿氏病、帕金森氏病和阿尔茨海默氏病）的神经炎性成分发挥作用，因此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/或其他相关化合物的实验研究。对于一种几乎没有治疗选择的疾病，推动这种潜在治疗方法的必要性不容低估。总共有6万到10万人 据估计，在任何给定的时间，ALS在世界范围内都受到影响，并且该疾病的发病率约为每100，000人中有5至9人。仅治疗性hi ALS的市场潜力就为1亿至3亿美元。

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.