Novel CEHC Derivatives for Neuroinflamation

描述（由申请人提供）：维生素E（α-生育酚）制剂构成了数百万美元的美国市场。生育酚补充剂被广泛用于推定的健康益处和抗氧化特性;但这些补充剂几乎仅限于a-生育酚。生育酚生物学因以下事实而复杂化：在结构上不同于α-生育酚的其他生育酚形式（β-、γ-和δ-生育酚）作为天然人类饮食的一部分存在。此外，生育酚在体内代谢产生尚未充分研究的羧乙基-羟基苯并二氢吡喃（CEHC）产物。最近的研究表明，γ-生育酚及其类似物具有抗炎和其他活性，可用于治疗。俄克拉荷马州医学研究基金会（OMRF）的科学家与安可制药公司建立了合作伙伴关系。目的是开发具有上级的抗炎和其它活性的新的基于生育酚的结构。我们已经开始系统地评估天然生育酚类似物，其CEHC代谢产物和合成衍生物之间的结构-活性关系，目的是确定赋予生物效力的特征。这项奋进的最终目的是开发新的，可申请专利的化合物，抑制中枢神经系统内的神经炎症反应。为此，我们提出以下具体目标。具体目标1：为了确定色满头部基团的3、4和5位的合理衍生化是否会提高生物活性，将合成一系列的11个新的CEHC衍生物。衍生物将被设计为结合联合收割机最好的第一代分子的有益特征;并系统地测试取代基电子学，立体和极性对化合物生物活性的重要性。具体目标2：将使用已建立的EOC-20小胶质细胞培养试验评价在特定目的I下合成的化合物对TNF α刺激的小胶质细胞活化的拮抗作用。亚硝酸盐输出和前列腺素E2（PGE 2）的生产将被用作抗神经炎症活性的指标。CEHC衍生物的疗效将与基准非甾体抗炎药进行比较。该I期申请的目标是确定用于治疗神经炎性疾病的两种主要CEHC。在II期期间，将在肌萎缩侧索硬化症（ALS）的鼠模型（G93 A-SOD 1转基因小鼠）中进一步评价这些先导药物，该模型显示出稳健的神经炎性疾病特征。G93 A-SOD 1小鼠模型的成功和阿尔茨海默病（AD）相关小鼠模型的确证性试验将证明寻求研究性新药（IND）状态是合理的。

DESCRIPTION (provided by applicant): Vitamin E (alpha-tocopherol) formulations constitute a multi-million dollar US market. Tocopherol supplements are widely used for presumptive health benefits and antioxidant properties; but these supplements are almost exclusively restricted to a-tocopherol. Tocopherol biology is complicated by the fact that other tocopherol forms (beta-, gamma-, and delta-tocopherol), structurally distinct from a-tocopherol, exist as part of the natural human diet. Moreover tocopherols are metabolized in vivo to yield carboxyethyl-hydroxyl chromane (CEHC) products that have been insufficiently studied. Recent studies suggest that gamma-tocopherol and its analogs possess anti-inflammatory and other activities that could be harnessed therapeutically. Scientists at the Oklahoma Medical Research Foundation (OMRF) have established a partnership with Encore Pharmecuticals, Inc. for the purpose of developing novel tocopherol-based structures with superior anti-inflammatory and other activities. We have begun to systematically evaluate structure-activity relationships among natural tocopherol analogs, their CEHC metabolites, and synthetic derivatives, with the goal of determining features that impart biological potency. The ultimate purpose of this endeavor is to develop novel, patentable compounds that inhibit neuroinflammatory reactions within the centralnervous system. Toward this end we propose the following SPECIFIC AIMS. SPECIFIC AIM 1: An initial series ofeleven new CEHC derivatives will be synthesized in order to determine whether rational derivatization of the 3, 4 and 5 positions of the chromane head group will improve bioactivity. Derivatives will be designed to combine beneficial features of the best first-generation molecules; and to systematically test the significance of substituent electronics, sterics and polarity on compound bioactivity. SPECIFIC AIM 2: The compounds synthesized under SPECIFIC AIM I will be evaluated for antagonism of TNFa-stimulated microglial activation using an established EOC-20 microglial cell culture assay. Nitrite output and prostaglandin E2 (PGE2) production will be used as indicators of anti-neuroinflammatory activity. Efficacy of CEHC derivatives will be compared with that of benchmark nonsteroidal anti-inflammatory drugs. The goal of this Phase I application is to identify two lead CEHCs for treating neuroinflammatory disease. During Phase II these lead agents will be further evaluated in a murine model for amyotrophic lateral sclerosis (ALS), the G93A-SOD1 transgenic mouse, which demonstrates a robust neuroinflammatory disease profile. Success in the G93A-SOD1 mouse model and confirmatory testing in a relevant mouse model of Alzheimer's disease (AD) will justify pursuit of investigational new drug (IND) status.