Thiazolino-Pyridone Compounds as Novel Drugs for Tuberculosis

噻唑啉-吡啶酮化合物作为结核病新药

• 批准号: 10698829
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698829
• 关键词: Acute; Aerobic; Agar; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimycobacterial Agents; Antitubercular Antibiotics; Bacteria; Biological Availability; Cell Line; Cells; Combined Modality Therapy; Development; Disease; Drops; Drug Design; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Energy Metabolism; Explosion; Family; Future; Generations; Goals; Growth; Half-Life; HepG2; Hypoxia; In Vitro; Infection; Infectious Agent; Intellectual Property; Isoniazid resistance; Lead; Libraries; Licensing; Liver Microsomes; Lung infections; Marketing; Metabolic; Mission; Modeling; Mus; Mutation; Mycobacterium tuberculosis; Newly Diagnosed; Oral; Outcome; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Prevalence; Process; Production; Property; Pyridones; Regimen; Renaissance; Resistance; Respiration; Respiratory Chain; Risk; Safety; Series; Small Business Innovation Research Grant; Solubility; Spottings; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Tuberculosis; analog; aqueous; bactericide; clinically relevant; combat; commercial application; compliance behavior; cost; cytotoxicity; dosage; drug candidate; drug development; drug discovery; drug-sensitive; experimental study; functional group; human mortality; improved; in vitro activity; in vitro testing; in vivo; indexing; innovation; interest; isoniazid; lead candidate; lead optimization; meter; monocyte; mortality; mouse model; mutant; novel; novel drug class; novel therapeutics; phase 1 study; pre-clinical; resistant strain; scaffold; side effect; small molecule; standard of care; success; treatment duration; tuberculosis drugs; tuberculosis treatment

Project Summary/Abstract Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of mortality due to infection, globally. In 2020, 10 million people were newly diagnosed with TB and 1.5 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by drug-resistant Mtb strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitive TB (DS-TB), which leads to poor patient adherence. Treatment for DR-TB is even longer, ranging from 6-24 months typically, with 3, 4 or more antibiotics taken in combination. While the last decade has seen a TB drug development “renaissance,” including the discovery of bedaquiline, newly approved regimens still suffer from serious side effects and can be cost prohibitive. Therefore, new classes of drugs with new MoAs that can be combined with existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied an explosion of drug discovery targeting respiration in Mtb. In this application, Fimbrion proposes to develop a thiazolino-pyridone (TZP) small molecule series with growth inhibitory activity against Mtb as a novel drug for treating TB. While the target of this compound series is currently unknown, TZPs appear to act through disruption of Mtb respiration. Interestingly, current TZPs not only have direct antimycobacterial activity, but they can also potentiate the activity of isoniazid (INH), an important frontline TB antibiotic, even restoring INH activity against INH-resistant Mtb in vitro. Our primary goal in this project is to develop a first-in-class, orally bioavailable, antimycobacterial TZP compound that could become part of a new frontline TB drug regimen to help shorten the duration of treatment. Currently, our most potent TZP compounds have sub-micromolar growth inhibition potency in vitro, and favorable drug-like properties. Therefore, our primary Phase I goal will be to improve growth inhibition potency while maintaining and/or improving the drug-like properties of the lead compounds to enable testing of optimized compounds in an animal model of Mtb infection. Specifically, we will 1) use medicinal chemistry drug design strategies to improve in vitro potency, metabolic stability, and solubility, and will establish in vivo pharmacokinetic (PK) profiles (including oral bioavailability) for optimized TZPs in mice; and 2) investigate the in vitro and in vivo efficacy of prioritized lead TZPs and generate spontaneous mutants resistant to these compounds to better understand the bacterial target and MoA. As we have found that the antimycobacterial potency of our TZPs tracks with their ability to potentiate INH, we will continue to spot-check this secondary property throughout the optimization of our TZPs. Upon completion of this project, we expect to identify an advanced lead TZP compound with demonstrated efficacy in a mouse model of acute TB, which could be further developed in a future Phase II SBIR project as part of a combination therapy for treating both DS- and DR-TB.

项目摘要/摘要 结核病（TB）是由细菌结核病（MTB）感染引起的，是主要原因 由于感染而导致的死亡率。 2020年，有1000万人被新诊断为结核病和150万人 人们死于疾病。随着治疗结核病的努力，耐药性引起的感染的流行率 MTB 对一个或多个前线护理标准（SOC）抗生素具有抗性的菌株（DR-TB）正在增加， 部分原因是组合疗法的持续时间长（6个月）（4种抗生素）用于药物敏感TB（DS-TB）， 导致患者的依从性不佳。 DR-TB的治疗时间更长，通常从6-24个月范围 组合使用3、4个或更多的抗生素。虽然过去十年已经看到了结核病的药物开发 “文艺复兴”，包括发现Bedaquiline，新批准的方案仍然遭受严重影响 效果，可以禁止成本。因此，新的类药物和新的MOA可以与 迫切需要在管道中现有或新的结核病药物。 Bedaquiline的成功，破坏了 MTB中的能量代谢，并在减少DR-TB的治疗时间方面表现出了希望 MTB中靶向呼吸的药物发现的爆炸。在此应用中，fimbrion提出了开发 噻唑诺吡啶 - 吡啶酮（TZP）小分子系列，具有生长抑制活性对MTB，作为一种新的药物 治疗结核病。虽然该化合物系列的目标目前尚不清楚，但TZP似乎通过中断起作用 MTB呼吸。有趣的是，当前的TZP不仅具有直接的抗菌活性，而且还可以 潜在的Isoniazid（INH）的活性，这是一种重要的前线TB抗生素，甚至还原了INH活性 体外耐药的MTB。我们在这个项目中的主要目标是开发一流的，口头的生物利用度， 抗菌细菌TZP化合物可能成为新的前线结核病药物方案的一部分，以帮助缩短 治疗持续时间。目前，我们最有效的TZP化合物具有亚微摩尔生长抑制效力 体外和有利的药物样特性。因此，我们的主要I阶段目标是改善增长抑制 在维持和/或改善铅化合物的药物样特性的同时，以实现测试 MTB感染动物模型中优化化合物。具体来说，我们将1）使用医学化学药物 设计策略以改善体外效力，代谢稳定性和可溶性，并将在体内建立 用于优化小鼠的TZP的药代动力学（PK）剖面（包括口服生物利用度）； 2）调查IN 优先铅TZP的体外和体内效率 化合物可以更好地了解细菌靶标和MOA。正如我们发现抗菌细菌 我们的TZPS轨道具有增强INH的能力的能力，我们将继续发现这一次要的 整个TZP的整个优化的属性。该项目完成后，我们希望确定 高级铅TZP化合物在急性结核的小鼠模型中具有效率，可以进一步 在未来的II期SBIR项目中开发，是用于治疗DS-和DR-TB的组合疗法的一部分。