Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis

项目概要/摘要 1结核病（TB），由结核分枝杆菌（Mtb）感染引起，是一种主要的结核病。 在全球范围内，感染是导致死亡的两大原因。2019年，1000万人被新诊断患有结核病， 300万人死于该病。随着结核病治疗工作的扩大， 4例耐药结核分枝杆菌 5的增加，部分原因是由于长期（6个月）的联合治疗（4种抗生素）的药物敏感性 6 TB（DS-TB），导致依从性差。耐药结核病的治疗时间甚至更长，从6-24个月不等 7通常，与3，4或更多的抗生素联合服用。尽管迫切需要新的治疗方法， 8耐药结核病，只有一种具有全新作用机制（MoA）的结核病新抗生素已于2009年获得批准。 9过去40年，贝达奎林。因此，具有新MoA的新药物类别可以与 迫切需要10种现有或新的结核病药物。贝达喹啉的成功， 11结核分枝杆菌的能量代谢，并已显示出减少耐药结核病治疗时间的前景， 12针对结核分枝杆菌呼吸的药物发现爆炸。Fimbrion正在开发一种噻吩并嘧啶小 靶向Mtb QcrB蛋白的13个分子系列 14电子传递链，已通过QcrB的早期临床成功被验证为药物靶标 15抑制剂，Q203，目前处于2期临床试验，但有潜在的责任。我们在这个项目中的目标是 16开发一种同类最佳的QcrB抑制剂，可以成为有效治疗糖尿病的较短药物方案的一部分。 17例为耐药性结核病和耐药结核病。最初在我们的第一阶段项目中，我们有一些非常有效的化合物， 18代谢稳定性差。因此，我们的第一阶段目标是优化稳定性，同时保持或 19提高效力，这样我们就可以在结核杆菌感染的动物模型中测试先导化合物。我们实现 20这一目标，确定了一个领先的THP系列稳定的QcrB抑制剂，具有低nM效力，有利的PK性质， 21，包括口服生物利用度，并在急性TB感染的小鼠模型中证明了体内功效。在我们 22第二阶段项目，我们将优化我们的铅系列，目标是识别和降低临床候选人的风险 23分子，有效治疗结核病。具体而言，我们将1）进一步优化我们的铅系列，以提高药物- 24类似的性质和药代动力学，同时保持或改善我们目前的体外效力和体内 i）先导化合物针对不同的Mtb菌株和在临床条件下的Mtb菌株的功效; ii）耐药性的风险，iii）与其他抗Mtb药物的潜在体外协同作用，以及iv）在 27体外毒性和潜在的不良药物-药物相互作用;和3）测试先进的先导化合物的疗效， 28种临床相关的TB疾病小鼠模型，并在较大的哺乳动物中评估体内PK和毒性，以选择 第29章去冒险该项目的成功完成将导致确定一个临床 30种候选药物将进行IND前研究，并吸引潜在的共同开发伙伴的兴趣。 对一种或多种一线标准治疗（SoC）抗生素耐药的耐药菌株（DR-TB） 用于治疗肺结核。QcrB，呼吸系统的一个组成部分，

Project Summary/Abstract 1 Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading 2 cause of mortality due to infection, globally. In 2019, 10 million people were newly diagnosed with TB and 1.5 3 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by 4 drug-resistant Mtb 5 is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitve 6 TB (DS-TB), which results in poor compliance. Treatment for DR-TB is even longer, ranging from 6-24 months 7 typically, with 3, 4 or more antibiotics taken in combination. Despite the dire need for new treatments against 8 DR-TB, only one new antibiotic for TB with an entirely novel mechanism of action (MoA) has been approved in 9 the past 40 years, bedaquiline. Therefore, new classes of drugs with new MoAs that can be combined with 10 existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts 11 energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied 12 an explosion of drug discovery targeting respiration in Mtb. Fimbrion is developing a thienopyrimidine small 13 molecule series that targets the Mtb QcrB protein 14 electron transport chain in Mtb, has been validated as a drug target by the early clinical success of the QcrB 15 inhibitor, Q203, which is currently in Phase 2 clinical trials, but has potential liabilities. Our goal in this project is 16 to develop a best-in-class QcrB inhibitor that could become part of a shorter drug regimen that effectively treats 17 both DS- and DR-TB. Initially in our Phase I project, we had examples of some very potent compounds, but 18 metabolic stability was poor. Our Phase I goals, therefore, were to optimize stability, while maintaining or 19 improving potency, so that we could test lead compounds in an animal model of Mtb infection. We achieved 20 this goal, identifying a lead THP series of stable QcrB inhibitors with low nM potency, favorable PK properties, 21 including oral bioavailability, and demonstrated in vivo efficacy in a mouse model of acute TB infection. In our 22 Phase II project, we will optimize our lead series with the goal of identifying and de-risking a clinical candidate 23 molecule that is effective in treating TB. Specifically, we will 1) further optimize our lead series to improve drug- 24 like properties and pharmacokinetics, while maintaining or improving our current in vitro potency and in vivo 25 efficacy; 2) investigate: i) the efficacy of lead compounds against diverse Mtb stains and under clinically 26 relevant conditions, ii) the risk of resistance, iii) potential in vitro synergy with other anti-Mtb drugs, and iv) in 27 vitro toxicity and potential adverse drug-drug interactions; and 3) test advanced lead compounds for efficacy in 28 clinically relevant mouse models of TB disease and assess in vivo PK and toxicity in larger mammals to select 29 and de-risk a clinical candidate. Successful completion of this project will lead to the identification of a clinical 30 candidate drug that will proceed to pre-IND studies and attract interest from potential co-development partners. strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics for the treatment of TB. QcrB, a component of the respiratory