Dipiperidines as a new class of anti-TB drug

二哌啶作为新型抗结核药物

• 批准号: 6791830
• 负责人: MARINA N PROTOPOPOVA
• 金额: $ 29.95万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791830
• 关键词: Mycobacterium tuberculosis; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; high performance liquid chromatography; laboratory mouse; macrophage; mass spectrometry; nuclear magnetic resonance spectroscopy; pharmacokinetics; piperidine; receptor binding; respiratory disorder chemotherapy; respiratory pharmacology; tuberculosis

DESCRIPTION (provided by applicant): The overall aim of this application is to characterize a new class of drugs to treat tuberculosis (TB) that are structurally unrelated to any existing anti-TB drugs. Three years ago, Sequella received a Challenge grant to synthesize and characterize combinatorial libraries of analogues to ethambutol, an existing front-line tuberculosis drug. While we did identify several promising ethambutol analogues that we are taking forward as a result of this work (our first lead compound is in preclinical toxicology studies in preparation for an IND-submission), we also identified a new class of compounds that are essentially structurally unrelated to ethambutol. This class of compounds has not previously been described, and several representatives of this class have excellent activity against M. tuberculosis in vitro. In this application, we propose to use an integrated approach to characterize these active compounds, then develop and refine them into lead molecules that have potential for therapeutic usage in TB. Briefly, we will use combinatorial chemistry to create a targeted library of analogues around to improve upon the desirable characteristics, building on our previous success with this approach. Chemical, biological, and pharmacological data will be used to develop desired profiles of the selected lead series; refinement of the series will result in candidates for further characterization and preclinical development. The process and the specific aims are highly iterative, and lessons learned from later aims will be cycled back to Specific Aim I to assist in the design of more active compounds.

描述（由申请人提供）：本申请的总体目标是描述一类新的治疗结核病（TB）药物的特征，该药物在结构上与任何现有的抗结核药物无关。三年前，Sequella 获得了一项挑战赛资助，用于合成和表征乙胺丁醇类似物的组合库，乙胺丁醇是一种现有的一线结核病药物。虽然我们确实确定了几种有前途的乙胺丁醇类似物，我们正在将其作为这项工作的结果进行推进（我们的第一个先导化合物正在进行临床前毒理学研究，为 IND 提交做准备），但我们还确定了一类在结构上与乙胺丁醇本质上无关的新化合物。此类化合物以前没有被描述过，并且此类化合物的几种代表在体外具有优异的抗结核分枝杆菌活性。在此应用中，我们建议使用综合方法来表征这些活性化合物，然后将它们开发并精炼成具有治疗结核病潜力的先导分子。简而言之，我们将利用组合化学来创建一个有针对性的类似物库，以改进所需的特性，在我们之前使用这种方法取得成功的基础上。化学、生物和药理学数据将用于开发所选先导系列的所需概况；该系列的完善将产生用于进一步表征和临床前开发的候选药物。该过程和具体目标是高度迭代的，从后续目标中吸取的经验教训将循环回到具体目标 I，以协助设计更具活性的化合物。

项目成果

Identification of SQ609 as a lead compound from a library of dipiperidines.

• DOI: 10.1016/j.bmcl.2011.07.015
• 发表时间: 2011-09-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Bogatcheva, Elena;Hanrahan, Colleen;Nikonenko, Boris;de los Santos, Gladys;Reddy, Venkata;Chen, Ping;Barbosa, Francis;Einck, Leo;Nacy, Carol;Protopopova, Marina
• 通讯作者: Protopopova, Marina