Highly Diverse and Structurally Varied Heterocyclic Libraries for the MLSMR

MLSMR 高度多样化且结构多样的杂环文库

• 批准号: 7493394
• 负责人: Richard Allen Houghten
• 金额: $ 45.9万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-05 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493394
• 关键词: Amitrole; Biological; Chemicals; Chemistry; Collection; Databases; Equilibrium; Equipment; Fluorine; Goals; Guanidines; Heterocyclic Compounds; Human Resources; Imines; Individual; Indoles; Institutes; Laboratories; Libraries; Medical Research; Methodology; Methods; Molecular; Molecular Bank; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Piperazines; Play; Preparation; Probability; Process; Property; Protocols documentation; Publishing; Research; Research Personnel; Role; S Phase; Screening procedure; Solid; Solubility; Solutions; Steroids; United States National Institutes of Health; Urea; base; cyclic compound; design; diketopiperazine; guanidinium; indole; indoline; novel; pharmacophore; piperazine; piperidine; repository; size; small molecule; small molecule libraries; solid solution; success

We plan to use our expertise in the diversity oriented synthesis of small molecule compounds for the preparation of 18-22 structurally unique pharmacophores. Many of the proposed strategies and synthetic approaches have already been optimized and published, thus increasing the probability of success. The proposed pharmacophores will be generated using solid and solution phase methods. The synthetic approaches to be pursued, while direct and productive, are highly practical and reproducible. The proposed compounds will significantly enhance the MLSMR collection. We will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds. Solid phase synthesis will be used to generate triazinediones, guanidino-ureas, aminotetrazoles, indolines, aminotriazoles, azoniaspiro, oxopiperazinium, and bis-cyclic compounds. We will use solution phase chemistry to produce novel indole, piperidine, tetrahydroquinoline, and steroid libraries. Additionally, we will develop synthetic approaches for the synthesis of unique organofluorinated compounds including DD-difluorocarbonyl compounds and varied difluoro-tetrahydropyrimidine derivatives. Fluorine-containing compounds have played a special role in medicinal chemistry and biomedical applications due to the unique influence of fluorine atoms on biological activity. In keeping with the themes of the investigator's research, we will target libraries of "Favored Pharmacophores" and employ the "Heteroatom Incorporation Strategy (HIS)" to generate novel libraries using diversity-oriented synthesis. The libraries are designed in a manner to balance size, diversity and complexity, and to optimize purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed to follow known drug-likeness rules including 'Lipinski's Rule of Five'. All structurally unique libraries will consist of 100-200 individual compounds (10 to 20 mg of each) and will be prepared with purity equal or higher than 90% as required by the RFA. These will be transferred to the repository with detailed experimental protocols and solubility information. The libraries proposed were selected in a manner which does not overlap in chemical space with molecules currently in the PubChem database. The majority of the chemistries are well established in the Pi's and Co-Pi's laboratories. There has been and continues to be, a longstanding collaborative interaction between the Pis at Torrey Pines Institute for Molecular Studies and the Burnham Institute for Medical Research, which is part of the Molecular Library Screening Center Network (MLSCN). We thus have ready access to equipment and personnel at both organizations and to the MLSCN.

我们计划利用我们在小分子化合物的多样性导向合成方面的专业知识， 制备18-22个结构独特的药效基团。许多提出的策略和综合 方法已经被优化并发布，从而增加了成功的可能性。这 所提出的药效团将使用固相和溶液相方法产生。合成的 所采取的方法虽然直接、富有成果，但具有高度实用性和可重复性。这 所提出的化合物将显着增强 MLSMR 收集。 我们将采用不同的策略面向多样性合成多种独特的杂环 化合物。固相合成将用于生成三嗪二酮、胍基脲、 氨基四唑、二氢吲哚、氨基三唑、azoniaspiro、氧代哌嗪和双环化合物。我们 将利用溶液相化学生产新型吲哚、哌啶、四氢喹啉和类固醇 图书馆。此外，我们将开发合成独特的有机氟化物的合成方法 化合物包括DD-二氟羰基化合物和各种二氟四氢嘧啶衍生物。 含氟化合物在药物化学和生物医学中发挥着特殊的作用 由于氟原子对生物活性的独特影响而得到广泛应用。符合主题 在研究者的研究中，我们将针对“喜爱的药效团”库并采用 “杂原子掺入策略（HIS）”使用面向多样性的合成生成新颖的文库。 文库的设计旨在平衡大小、多样性和复杂性，并优化纯度。 这对于避免筛查过程中的误报至关重要。所有提议的小分子 库的设计遵循已知的药物相似规则，包括“Lipinski 的五规则”。全部结构上 独特的文库将包含 100-200 种单独的化合物（每种化合物 10 至 20 毫克），并将进行制备 根据 RFA 的要求，纯度等于或高于 90%。这些将被转移到存储库 具有详细的实验方案和溶解度信息。 所提议的文库的选择方式与化学空间不重叠。 目前在 PubChem 数据库中的分子。大多数化学物质在 Pi 和 Co-Pi 的实验室。长期的协作互动已经并将继续存在 多利派恩斯分子研究所和伯纳姆医学研究所的 Pis 之间 研究是分子图书馆筛选中心网络 (MLSCN) 的一部分。这样我们就准备好了 访问两个组织和 MLSCN 的设备和人员。