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）是由细菌结核菌（MTB）感染引起的，是领先的 单一传染毒剂的世界死亡率。随着治疗结核病的努力的扩大， 耐多药TB（MDR-TB），对前线护理标准（SOC）抗生素有抗性 利福平和异念珠菌正在增加。尽管迫切需要针对抗药性结核病的新治疗 在过去的40年中，一类新类的抗生素已进入诊所接受MDR-TB的治疗，并 Bedaquiline获得的批准药物具有重大副作用，包括死亡。因此，新的 以与现有药物敏感TB和MDR-TB SOC协同作用的方式针对MTB的药物类别 迫切需要疗法。为此，fimbrion已确认了一系列的知识产权 具有抑制性和杀菌活性对MTB体外的杂环化合物。这项技术起源 华盛顿大学和圣路易斯大学，这些系列中最有力的成员有 低纳摩尔范围内抑制剂浓度（IC50）的活性。该化合物系列的目标是 QCRB蛋白是MTB中呼吸电子传输链的组成部分，表明这些化合物是 通过破坏呼吸来抑制MTB的生长和生存。 QCRB最近被确定为可行 治疗结核病的药物目标，但我们的化合物系列与一个QCRB相比具有独特的结构 抑制剂，Q203，目前正在临床试验中，我们的化合物在体外具有杀菌活性 尚未报告Q203的杀菌活性。虽然该脚手架的许多理化学特性是 适合药物开发，我们产生了一些非常有效的化合物，低代谢稳定性 到目前为止，已经是责任。因此，优化稳定性，同时保持效力，将是我们的优先事项 化学优化工作。主要目标或我们的项目建议是开发一系列小说 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 在MTB感染的动物模型中治疗结核病。为了实现这一目标，我们将扩展我们的化合物库， 专注于两个杂环的子类，以发现和优化候选铅系列 代谢稳定性提高，同时保持效力并最大程度地减少细胞毒性。正确直接导线 串联识别和优化，我们将最初选择早期铅化合物，然后以后优化铅 体内PK具有高效力和稳定性的串联化合物。候选人以有利的PK领导 轮廓将测试针对10种不同药物敏感和MDR MTB菌株的集合的体外活性 以及与Bedaquiline协同作用，它也针对MTB呼吸。然后，我们将执行证明 测试高级铅序列化合物是否在体内功效中是否具有体内功效的主要实验 急性MTB肺部感染的动物模型。拟议的研究有可能导致发展 抗药性和耐药性结核病的新型抗菌细菌家族。