Synthesis And Anticonvulsant Evaluation Of Enaminones

烯胺酮的合成及抗惊厥作用评价

• 批准号: 6636686
• 负责人: KENNETH R SCOTT
• 金额: $ 18.87万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-10 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636686
• 关键词: X ray crystallography; anticonvulsants; biological transport; blood brain barrier; chemical models; chemical structure function; computer simulation; cyclic amine; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; high performance liquid chromatography; laboratory rat; lead; molecular dynamics; pharmacokinetics

Description (Adapted from Application): The specific aims of the project are to synthesize new chemical compounds and evaluate them for anticonvulsant activity. The long-term objectives include the discovery of new classes of anticonvulsant agents and the development of better anticonvulsant compounds that will lack the adverse effect of currently used antiepileptic agents. Currently, no chemical entity or surgical intervention has offered a complete cure for all types of epilepsy. The research plan is designed to exploit, in a systematic manner, two interesting and hitherto unique lead moieties developed in the investigators laboratories: the cyclic enaminones; and the spiroimidooxy analogs. The experimental design comprises the synthesis of new compounds of each moiety by procedures previously reported in this laboratory, with appropriate modifications. In addition, molecular modeling techniques will be employed, and the Free-Wilson analysis as detailed by P.N. Craig (J. Med. Chem. 1971, 14, 680-684 and J. Med. Chem. 1972, 15, 144-149) will be used in the development of quantitative structure-activity relationships for each moiety. Further, the new moieties and the previous analogs will be analyzed by comparative molecular field analysis-X-ray structure analysis, and in vivo determinations of the pharmacokinetics of transport of various active and inactive derivatives across the blood-brain barrier in rats will be undertaken in collaborating laboratories. An in-depth evaluation of these new classes of anticonvulsants is therefore warranted in order to study the relationship between electronic, steric, and lipophilic effects to anticonvulsant activity and pharmacokinetics so that a predictive mechanism for the feasibility of further synthetic efforts may be justified.

描述（改编自申请）：该项目的具体目标是 合成新化合物并评估其抗惊厥作用 活动。长期目标包括发现新类别 抗惊厥药物和更好的抗惊厥化合物的开发 这不会产生目前使用的抗癫痫药物的副作用。 目前，还没有任何化学实体或外科手术可以提供完整的治疗方法。 治愈所有类型的癫痫症。该研究计划旨在利用 系统地，开发了两个有趣且迄今为止独特的先导部分 在研究人员的实验室中：环状烯胺酮；和 螺亚胺氧基类似物。实验设计包括合成新的 通过本实验室先前报告的程序对每个部分的化合物进行分析， 经过适当的修改。此外，分子建模技术将 被采用，以及 P.N. 详细介绍的 Free-Wilson 分析。克雷格 (J. Med. 化学。 1971, 14, 680-684 和 J. Med。化学。 1972, 15, 144-149）将用于 每个的定量结构-活性关系的发展 部分。此外，新的部分和先前的类似物将通过以下方法进行分析： 比较分子场分析-X射线结构分析，以及体内 各种活性物质转运的药代动力学测定 将在大鼠中进行跨血脑屏障的无活性衍生物 在合作实验室。对这些新类别的深入评估 因此，为了研究这种关系，需要使用抗惊厥药物 电子、空间和亲脂效应与抗惊厥活性之间的关系 和药代动力学，以便预测机制的可行性 进一步的综合努力可能是合理的。