REACTOR FOR GENERATION OF COMPOUND DERIVATIVE LIBRARIES

用于生成化合物衍生库的反应器

• 批准号: 6180674
• 负责人: James B. West
• 金额: $ 39.45万
• 依托单位: BEND RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180674
• 关键词: bioreactors; chemical registry /resource; chemical structure; chemical synthesis; combinatorial chemistry; high performance liquid chromatography; mass spectrometry; technology /technique development

This goal of this program is to develop a new process for rapidly generating mixtures of derivatives (i.e., derivative libraries) with chemical structures that are based on the structure of a single bioactive parent compound. The proposed process makes it possible to produce structurally distinct derivatives rapidly and to produce derivatives not readily accessible from the parent compound using traditional chemical methods. The process promises to greatly accelerate the optimization and development of pharmaceutical leads. In Phase I, we demonstrated feasibility by producing chemical libraries that contained 50 or more derivative compounds based on two parent structures: caffeine and xanthine. The library reactions were reproducible, and specific compounds were produced in sufficient amounts to allow isolation, testing, and structural characterization. These libraries were shown to contain bioactive compounds and were suitable for use with high- throughput screening. Phase II work will focus on development of the process through extensive structural elucidation of new, more chemically diverse libraries. The effects of various derivatizing molecules and preparation variables will be examined. Bend Research plans to develop a business based on this technology that will produce custom libraries for pharmaceutical clients and provide further services of isolation and structural elucidation of promising compounds. PROPOSED COMMERCIAL APPLICATION This process would provide a new, inexpensive method for rapidly generating libraries of compounds that are closely related to pharmaceutically active parent compounds but that differ in a direct structural feature. Successful implementation could significantly reduce the time and effort required to generate pharmaceutically valuable derivatives from parent compounds. Due to its speed and potential for forming classes of derivatives not readily accessible by traditional chemical methods, this process has breakthrough potential for increasing the efficiency of drug discovery.

该计划的目标是开发一种新工艺，用于快速生成具有基于单一生物活性母体化合物结构的化学结构的衍生物混合物（即衍生物库）。 所提出的方法使得能够快速生产结构不同的衍生物，并生产使用传统化学方法不易从母体化合物获得的衍生物。 该过程有望大大加速先导药物的优化和开发。在第一阶段，我们通过生成包含 50 种或更多基于咖啡因和黄嘌呤两种母体结构的衍生化合物的化学库来证明可行性。 库反应是可重复的，并且产生了足够量的特定化合物以允许分离、测试和结构表征。 这些文库显示含有生物活性化合物，适合用于高通量筛选。第二阶段的工作将侧重于通过对新的、化学上更加多样化的文库进行广泛的结构阐明来开发该工艺。 将检查各种衍生分子和制备变量的影响。 Bend Research 计划开发基于该技术的业务，为制药客户生产定制库，并提供有前景化合物的分离和结构解析的进一步服务。拟议的商业应用该过程将提供一种新的、廉价的方法来快速生成与药物活性母体化合物密切相关但在直接结构特征上不同的化合物库。 成功实施可以显着减少从母体化合物生成具有药学价值的衍生物所需的时间和精力。 由于其形成传统化学方法不易获得的衍生物类别的速度和潜力，该过程在提高药物发现效率方面具有突破性潜力。