Stereochemically and Structurally Diverse Pilot Scale Libraries for the MLSMR

MLSMR 立体化学和结构多样化的中试规模文库

• 批准号: 7289762
• 负责人: Richard Allen Houghten
• 金额: $ 43.91万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289762
• 关键词: Benzimidazoles; Carbolines; Chemicals; Chemistry; Collection; Databases; Equilibrium; Equipment; Ethylenethiourea; Goals; Guanidines; Heterocyclic Compounds; Human Resources; Individual; Institutes; Laboratories; Lead; Libraries; Medical Research; Methodology; Methods; Molecular; Molecular Bank; Molecular Weight; Numbers; Pharmaceutical Preparations; Phase; Piperazines; Preparation; Process; Property; Range; Screening procedure; Solid; Solubility; Solutions; United States National Institutes of Health; base; benzimidazole; design; diketopiperazine; guanidinium; imidazolone; novel; pharmacophore; piperazine; repository; size; small molecule; small molecule libraries; solid solution

DESCRIPTION (provided by applicant): We plan to use our collective long standing expertise in the diversity oriented synthesis of small molecule compounds for the preparation of a range of 20-26 structurally unique pharmacophores. The proposed strategies and synthetic approaches will lead in a predictable fashion to diversities of multiple chemical probes and will generate a variety of compound types. We will employ both solid and solution phase methods. The synthetic approaches to be pursued while direct and productive, are highly practical and reproducible. The target compounds will therefore be unique and will capitalize on our strength in the utilization of synthetic "simplicity" for the design and the successful parallel synthesis of large numbers of compounds. Thus, we will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds that will enrich the MLSMR collection of small molecules. Compounds will include differing diaza and triazacyclic compounds and diverse fused heterocyclic compounds such as triazinobenzimidazoles and novel fused tetra and pentacyclic o-carbolines [sic]. In addition, one of the approaches we will use in this application is to 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, complexity and purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed with regard to known drug-likeness rules including 'Lipinski's Rule of Five'. All structurally unique libraries will consist of 100-200 individual compounds each and will be prepared with purity equal or higher than 90%. As required by the RFA, 10 to 20 mg of each compound will be prepared and transferred to the NIH small Molecule Repository with the detailed synthetic experimental information and solubility properties. The libraries proposed are designed in a manner which balances molecular weight, diversity, complexity and purity. These have been chosen 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.

描述（由申请人提供）：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集体长期专业知识，制备20-26种结构独特的药效团。 所提出的策略和合成方法将以可预测的方式导致多种化学探针的分离，并将产生多种化合物类型。我们将采用固相法和液相法。 所要追求的合成方法虽然直接且多产，但具有高度实用性和可再现性。 因此，目标化合物将是独特的，并将利用我们在利用合成“简单性”进行设计和成功平行合成大量化合物方面的优势。 因此，我们将使用不同的策略，以多样性为导向的合成各种独特的杂环化合物，这将丰富MLSMR收集的小分子。 化合物将包括不同的二氮杂和三氮杂环化合物和不同的稠合杂环化合物，如三嗪基苯并咪唑和新的稠合四环和五环邻-咔啉[原文如此]。此外，我们将在本申请中使用的方法之一是靶向FXR药效团的文库，并采用杂原子掺入策略（HIS）来使用多样性导向的合成产生新的文库。 文库的设计方式是平衡大小、多样性、复杂性和纯度。 这对于避免筛选过程中的假阳性至关重要。 所有提出的小分子文库都是根据已知的药物相似性规则（包括“Lipinski's Rule of Five”）设计的。 所有结构独特的文库将各自由100-200种单独的化合物组成，并且将以等于或高于90%的纯度制备。 根据RFA的要求，将制备10至20 mg的每种化合物，并将其转移至NIH小分子储存库，并提供详细的合成实验信息和溶解度特性。 建议的图书馆的设计方式是平衡 分子量、多样性、复杂性和纯度。 这些分子的选择方式不会与PubChem数据库中目前的分子在化学空间上重叠。大多数 PI和Co-PI的实验室中已建立了良好的化学反应。Torrey Pines分子研究所和Burnham医学研究所的PI之间一直存在并将继续存在长期的合作互动，该研究所是分子库筛选中心网络（MLSCN）的一部分。因此，我们可以随时获得这两个组织的设备和人员，并可以随时进入劳动和安全合作网络。