Novel QcrB Inhibitors for the Treatment of Tuberculosis

摘要 结核病(TB)是由结核分枝杆菌(Mtb)引起的最大杀手。 传染病。结核病也是与抗菌剂有关的所有死亡的四分之一的原因。 抗性(AMR)。据预测，到2050年，7500万人，或者说每12秒就有一人， 将死于与结核病相关的AMR。治疗时间长，抗药性增强 药物催生了寻找治疗时间更短和新奇的新化合物的需求 行动机制。三唑嘧啶(TZP)化合物可能导致疗程缩短 因为它们对复制型和非复制型结核分枝杆菌都有效，并且可以解决 耐药，因为它们针对的是QcrB(泛醌细胞色素C氧化还原酶)，一种蛋白质 目前没有针对现有的结核病药物。在第一阶段，我们建议优化 TZP系列的物化性质和ADME-PK性质及其影响的研究 与贝达奎林等其他呼吸抑制药联合使用。我们将鉴定化合物 具有合适的效力、体内暴露和耐受性。我们将使用一种优化的化合物来 在结核病感染的动物模型中展示有效性，我们将确定杀灭动力学和 化合物单独及与其他呼吸系统药物联合应用的生长抑制特性 复制和非复制条件下的抑制剂。 在这些研究的结论中，我们将证明TZP系列，在 与其他呼吸抑制剂联合使用，可缩短治疗时间。我们会有 完成了一项概念验证动物研究，以证明体内疗效。在第二阶段，我们 将完成先导优化，进一步表征生物活性，并在体内扩展 学习。

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the biggest killer among infectious diseases. TB is also responsible for a quarter of all deaths associated with Antimicrobial Resistance (AMR). It is projected that by 2050, 75 million people, or one person every 12 seconds, will die due to AMR associated with TB. Long treatment times and increasing resistance to TB drugs have created the need to find new compounds with shorter treatment times and novel mechanisms of action. Triazolopyrimidine (TZP) compounds may lead to treatment shortening because they are effective against both replicating and non-replicating Mtb, and may address drug resistance because they target QcrB (ubiquinone cytochrome C oxidoreductase), a protein not currently targeted with existing TB drugs. During Phase I, we propose to optimize the physicochemical and ADME-PK properties of the TZP series and study the effects of this series in combination with other respiratory inhibitors such as bedaquiline. We will identify compounds with suitable potency, in vivo exposure, and tolerability. We will use an optimized compound to demonstrate efficacy in an animal model of TB infection and we will determine the kill kinetics and growth inhibition properties of the compounds alone and in combination with other respiratory inhibitors under replicating and non-replicating conditions. At the conclusion of these studies, we will have demonstrated feasibility that the TZP series, in combination with other respiratory inhibitors, results in treatment shortening. We will have completed a proof of concept animal study to demonstrate in vivo efficacy. During Phase II, we will complete lead optimization, further characterize the biological activity, and expand in vivo studies.