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: 7291301
• 负责人: Richard Allen Houghten
• 金额: $ 48.76万
• 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/7291301
• 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

DESCRIPTION (provided by applicant): 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-investigator's laboratories. There has been, and continues to be, a long-standing 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.

描述（由申请人提供）：我们计划在小分子化合物的多样性综合中使用我们的专业知识，以制备18-22个结构独特的药理。 许多提出的策略和合成方法已经进行了优化和发布，从而增加了成功的可能性。 拟议的药理将使用固体和溶液相的方法生成。 虽然直接和富有成效的综合方法是高度实用和可重复的。 所提出的化合物将显着增强MLSMR收集。 我们将使用不同的策略来构成各种独特的杂环化合物的综合。 固相合成将用于产生三酶，鸟翼蛋白，氨基二唑唑，吲哚，氨基三位生，氨基替二唑，苯二氮，氧化脂蛋白，氧化脂蛋白和二一个化合物。 我们将使用溶液相化学生成新颖的吲哚，哌啶，四氢喹啉和类固醇库。 此外，我们将开发合成的方法，用于合成独特的有机荧光化合物，包括DD-二氟苯丙基化合物和各种二氟二氢吡啶衍生物。 含氟化合物在药物化学和生物医学应用中发挥了特殊作用，这是由于氟原子对生物活性的独特影响。 为了符合研究者研究的主题，我们将针对“受青睐的药算师”的图书馆，并采用“ Heteroatom Incorputation策略（HIS）”来使用面向多样性的合成来生成新的库。 图书馆的设计方式可以平衡规模，多样性和复杂性，并优化纯度。 这对于避免在筛选过程中避免误报至关重要。 所有拟议的小分子库旨在遵循已知的毒品规则，包括“ Lipinski的五个规则”。 所有结构上独特的库将由100-200种单独的化合物（每种10至20 mg）组成，并根据RFA要求的纯度等于或高于90％。 这些将通过详细的实验协议和溶解度信息转移到存储库。 提出的图书馆是以与当前在PubChem数据库中的分子重叠的方式选择的。 大多数化学物质都在PI和共同投资者的实验室中良好确定。 托里·派恩斯分子研究研究所的PIS与伯纳姆医学研究所（MLECULAL图书馆筛选中心网络（MLSCN）的一部分）之间存在并且继续存在，并且继续存在。 因此，我们可以准备在两个组织和MLSCN的设备和人员访问。