REACTOR FOR GENERATION OF COMPOUND DERIVATIVE LIBRARIES

用于生成化合物衍生库的反应器

• 批准号: 6015644
• 负责人: James B. West
• 金额: $ 39.95万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015644
• 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快速生成衍生物混合物的新方法（即，衍生物库），其化学结构基于单一生物活性母体化合物的结构。 所提出的方法可以快速生产结构不同的衍生物，并生产使用传统化学方法不容易从母体化合物获得的衍生物。 这一过程有望大大加快制药先导产品的优化和开发。在第一阶段，我们通过生产包含50种或更多种基于两种母体结构的衍生化合物的化学库来证明可行性：咖啡因和黄嘌呤。 库反应是可再现的，并且以足够的量产生特定化合物以允许分离、测试和结构表征。 这些文库被证明含有生物活性化合物，并且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、化学上更多样化的文库进行广泛的结构阐明来开发该过程。 将检查各种衍生分子和制备变量的影响。弯曲研究计划开发一项基于该技术的业务，该业务将为制药客户生产定制库，并为有前途的化合物提供进一步的分离和结构解析服务。该方法将提供一种新的、廉价的方法，用于快速产生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文库。 成功的实施可以显著减少从母体化合物产生有药用价值的衍生物所需的时间和精力。 由于它的速度和潜力，形成的衍生物类别不容易通过传统的化学方法，这一过程具有突破性的潜力，提高药物发现的效率。