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一类新的治疗结核病(TB)的药物，这些药物在结构上与任何现有的抗结核病药物无关。三年前，Sequella获得了一项挑战拨款，用于合成和表征现有一线结核病药物乙胺丁醇类似物的组合库。虽然我们确实发现了几个有希望的乙胺丁醇类似物，但我们正在推进这项工作(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)，我们也发现了一类新的化合物，它们在结构上基本上与乙胺丁醇无关。这类化合物以前没有被描述过，而且这类化合物的几个代表在体外对结核分枝杆菌具有很好的活性。在这项应用中，我们建议使用一种综合的方法来表征这些活性化合物，然后将它们开发和提炼成具有治疗结核病潜力的铅分子。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，以改进所需的特征，建立在我们以前使用这种方法取得的成功的基础上。化学、生物和药理学数据将被用来开发所选铅系列的所需概况；该系列的改进将导致进一步表征和临床前开发的候选者。这一过程和具体目标是高度迭代的，从后来的目标中吸取的经验教训将循环回到具体目标一，以帮助设计更有活性的化合物。

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.