Dipiperidines as a new class of anti-TB drug

描述（由申请人提供）：本申请的总体目标是描述与任何现有抗结核药物结构无关的治疗结核病（TB）的新类别药物。三年前，Sequella获得了一项挑战拨款，用于合成和表征乙胺丁醇（一种现有的一线结核病药物）类似物的组合文库。虽然我们确实确定了一些有前途的乙胺丁醇类似物，我们正在推进这项工作（我们的第一个先导化合物正在临床前毒理学研究中，准备提交ind），我们还确定了一类与乙胺丁醇基本结构无关的新化合物。这类化合物以前没有被描述过，这类化合物的几个代表在体外对结核分枝杆菌有很好的活性。在这项应用中，我们建议使用一种综合方法来表征这些活性化合物，然后将它们开发和提炼成可能用于结核病治疗的铅分子。简而言之，我们将使用组合化学来创建一个有针对性的类似物库，以改进我们以前使用这种方法取得的成功。化学，生物学和药理学数据将用于开发选定的铅系列所需的概况；该系列的改进将产生进一步表征和临床前开发的候选药物。这个过程和特定目标是高度迭代的，从后来的目标中吸取的经验教训将循环回到特定目标I，以帮助设计更有效的化合物。

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.