Novel CEHC Derivatives for Neuroinflamation

描述(由申请人提供)：维生素E(α-生育酚)配方构成了数百万美元的美国市场。生育酚补充剂被广泛用于假定的健康益处和抗氧化特性；但这些补充剂几乎仅限于α-生育酚。生育酚生物学之所以复杂，是因为在结构上与α-生育酚不同的其他生育酚形式(β-生育酚、γ-生育酚和β-生育酚)作为人类天然饮食的一部分而存在。此外，生育酚在体内被代谢成羧乙基-羟基色曼(CEHC)产物，这些产物还没有得到充分的研究。最近的研究表明，γ-生育酚及其类似物具有抗炎和其他可用于治疗的活性。俄克拉荷马医学研究基金会(OMRF)的科学家与Encore制药公司建立了合作伙伴关系，目的是开发具有优异抗炎和其他活性的基于生育酚的新型结构。我们已经开始系统地评估天然生育酚类似物、它们的CEHC代谢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学效力的特征。这一努力的最终目的是开发新型的、可申请专利的化合物，以抑制中枢神经系统内的神经炎性反应。为此，我们提出以下具体目标。具体目的1：将首先合成11个新的CEHC衍生物，以确定有理的3、4和5位色胺头基的衍生化是否能提高生物活性。衍生物的设计将结合最好的第一代分子的有益特征；并系统地测试取代基电子、空间位阻和极性对化合物生物活性的重要性。特定目的2：利用建立的EOC-20小胶质细胞培养实验，评估在特定AIM I下合成的化合物对TNFa刺激的小胶质细胞激活的拮抗作用。亚硝酸盐的产生和前列腺素E2(PGE2)的产生将被用作抗神经炎活性的指标。CEHC衍生物的疗效将与基准非类固醇抗炎药进行比较。这一第一阶段应用的目标是确定两种主要的CEHC用于治疗神经炎症性疾病。在第二阶段，这些先导剂将在肌萎缩侧索硬化症(ALS)小鼠模型--G93A-SOD1转基因小鼠--中进一步评估，该模型显示出强大的神经炎症性疾病特征。在G93A-SOD1小鼠模型中的成功以及在阿尔茨海默病(AD)相关小鼠模型中的确证测试将证明追求研究新药(IND)的地位是合理的。

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.