Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis

QcrB 杂环抑制剂作为结核病新药

• 批准号: 9906022
• 负责人: THOMAS Joseph HANNAN
• 金额: $ 30万
• 依托单位: FIMBRION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-13 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906022
• 关键词: Active Sites; Acute; Address; Animal Model; Antibiotic Therapy; Antibiotics; Bacteria; Biological Assay; Cessation of life; Chemicals; Clinic; Clinical; Clinical Trials; Collection; Development; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Electron Transport; Ensure; Evaluation; Family; Goals; Government; Growth; Heterocyclic Compounds; In Vitro; Infection; Infectious Agent; Intellectual Property; Lead; Libraries; Literature; Lung infections; Measures; Metabolic; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Persons; Pharmaceutical Preparations; Prevalence; Property; Proteins; Pyrimidines; Reporting; Resistance; Respiration; Rifampin; Saints; Series; Solubility; Structure; Tail; Technology; Testing; Therapeutic; Toxic effect; Treatment Protocols; Tuberculosis; Universities; Washington; analog; bactericide; design; drug development; drug-sensitive; early phase clinical trial; experimental study; human mortality; improved; in vitro activity; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; isoniazid; lead candidate; lead optimization; lead series; lipophilicity; member; mortality; mouse model; mycobacterial; nanomolar; novel; novel drug class; novel therapeutics; preclinical development; respiratory; scaffold; screening; side effect; small molecule; standard of care; synergism; tuberculosis drugs; tuberculosis treatment

Tuberculosis (TB) is caused by infection with the bacterium Mycobacteria tuberculosis (Mtb) and is the leading cause of mortality in the world for a single infectious agent. As efforts to treat TB expand, the prevalence of multidrug resistant TB (MDR-TB), which are resistant to the frontline standard of care (SOC) antibiotics rifampicin and isoniazid, is increasing. Despite the dire need for new treatments against drug resistant TB, only one new class of antibiotics has made it into the clinic for treatment of MDR-TB in the past 40 years and the approved drug from this class, bedaquiline, has significant side effects, including death. Therefore, new classes of drugs that target Mtb in ways that synergize with existing drug sensitive TB and MDR-TB SOC therapies are desperately needed. To this end, Fimbrion has in-licensed the intellectual property for a series of heterocyclic compounds with inhibitory and bactericidal activity against Mtb in vitro. This technology originated at Washington University and Saint Louis University, and the most potent members of these series have activity at inhibitor concentrations (IC50) in the low nanomolar range. The target of this compound series is the QcrB protein, a component of the respiratory electron transport chain in Mtb, suggesting that these compounds inhibit Mtb growth and survival through disrupting respiration. QcrB has recently been identified as a viable drug target for treating TB, but our compound series has a unique structure compared to the one QcrB inhibitor, Q203, that is currently in clinical trials and our compounds have bactericidal activity in vitro, whereas bactericidal activity has not been reported for Q203. While many physiochemical properties of this scaffold are suitable for drug development and we have generated some very potent compounds, low metabolic stability has thus far been a liability. Therefore, optimizing stability, while maintaining potency, will be a priority of our chemical optimization efforts. The main goal or our project proposal is to develop a lead series of novel heterocyclic QcrB inhibitors with improved pharmacokinetic (PK) properties that will be capable of effectively treating TB in an animal model of Mtb infection. To achieve this goal, we will expand our library of compounds, focusing on two subclasses of heterocycles in order to discover and optimize candidate lead series with increased metabolic stability, while maintaining potency and minimizing cellular toxicity. To properly direct lead series identification and optimization, we will select early lead compounds initially and then later optimized lead series compounds with high potency and increased stability for in vivo PK. Candidate leads with favorable PK profiles will be tested for in vitro activity against a collection of 10 diverse drug-sensitive and MDR Mtb strains as well as for synergy with bedaquiline, which also targets Mtb respiration. We will then perform proof of principle experiments to test whether an advanced lead series compound can have in vivo efficacy in an animal model of acute Mtb lung infection. The proposed studies have the potential to result in the development of a new family of anti-mycobacterials for use against both drug-sensitive and drug-resistant TB.

结核病(TB)是由结核分枝杆菌(Mtb)感染引起的，是主要的 世界上单一传染病病原体的死亡原因。随着治疗结核病的努力扩大，结核病的流行 耐多药结核病(MDR-TB)，对一线治疗标准(SOC)抗生素耐药 利福平和异烟肼，正在增加。尽管抗药性结核病迫切需要新的治疗方法，但只有 在过去的40年里，一种新的抗生素已经进入临床，用于治疗耐多药结核病 这类批准的药物贝达奎林有显著的副作用，包括死亡。因此，新的 与现有药物敏感结核病和耐多药结核病SOC协同作用的针对结核分枝杆菌的药物类别 人们迫切需要治疗。为此，Fimbrion已为一系列 对结核分枝杆菌具有抑制和杀菌活性的杂环化合物。这项技术起源于 在华盛顿大学和圣路易斯大学，这些系列中最有影响力的成员 在低纳摩尔范围内的抑制剂浓度(IC50)下的活性。这个复合系列的目标是 QcrB蛋白是结核分枝杆菌呼吸电子传递链的一个组成部分，这表明这些化合物 通过干扰呼吸抑制结核分枝杆菌的生长和存活。QCRB最近被认为是一个可行的 用于治疗结核病的药物，但我们的化合物系列与QcrB相比具有独特的结构 目前正在进行临床试验的抑制剂Q203，我们的化合物在体外具有杀菌活性，而 Q203的杀菌活性尚未见报道。虽然这种支架的许多物理化学性质是 适合于药物开发，我们已经产生了一些非常有效的化合物，代谢稳定性低 到目前为止一直是一种负担。因此，优化稳定，同时保持效力，将是我们的优先事项 化学优化的努力。我们项目提案的主要目标是开发一系列领先的小说 具有改进的药代动力学(PK)特性的杂环QcrB抑制剂，将能够有效地 在结核分枝杆菌感染的动物模型中治疗结核病。为了实现这一目标，我们将扩大我们的化合物库， 专注于杂环的两个亚类，以发现和优化候选的先导系列 提高代谢稳定性，同时保持效力并将细胞毒性降至最低。适当地引导引线 系列鉴定和优化，我们首先选择早期的先导化合物，然后再优化先导化合物 用于体内PK的高效和增强稳定性的系列化合物。候选人PK支持率领先 将对10种不同的药物敏感和耐多药结核分枝杆菌菌株进行体外活性测试 以及与贝达奎兰的协同作用，贝达奎兰也针对Mtb呼吸。然后，我们将执行证明 测试一种先进的铅系列化合物是否可以在体内对癌症有效的原理实验 急性结核分枝杆菌肺部感染的动物模型。拟议的研究有可能导致这一发展 一种新的抗分枝杆菌药物家族，用于治疗药物敏感和耐药结核病。