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.

项目概要/摘要 结核病 (TB) 由结核分枝杆菌 (Mtb) 感染引起，是一个主要原因 2020 年，全球新诊断结核病人数为 1000 万人，新增确诊人数为 150 万人。 随着结核病治疗努力的扩大，耐药性引起的感染流行。 山地车 对一种或多种一线护理标准 (SoC) 抗生素耐药的菌株 (DR-TB) 正在增加， 部分原因是药物敏感结核病 (DS-TB) 的联合治疗（4 种抗生素）持续时间长（6 个月）， 这导致患者对耐药结核病的治疗依从性较差，通常需要 6 至 24 个月。 过去十年出现了结核病药物的开发。 “文艺复兴”，包括贝达奎林的发现，新批准的治疗方案仍然存在严重的副作用 因此，可以与新的 MoAs 结合使用的新类别药物。 迫切需要现有的或正在研发的新结核病药物贝达喹啉的成功，它扰乱了市场。 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希望，并伴随着 针对结核分枝杆菌呼吸的药物发现呈爆炸式增长。在该应用中，Fimbrion 提议开发一种 噻唑啉吡啶酮（TZP）小分子系列，具有抗 Mtb 生长抑制活性，作为治疗结核病的新药 虽然该化合物系列的目标目前尚不清楚，但 TZP 似乎通过破坏发挥作用。 Mtb 呼吸作用表明，目前的 TZP 不仅具有直接的抗分枝杆菌活性，而且还可以 增强异烟肼 (INH)（一种重要的一线结核病抗生素）的活性，甚至恢复 INH 的活性 我们在这个项目中的主要目标是开发一种一流的、口服生物可利用的 Mtb。 抗分枝杆菌 TZP 化合物可能成为新的一线结核病药物疗法的一部分，以帮助缩短治疗时间 目前，我们最有效的 TZP 化合物具有亚微摩尔生长抑制效力。 因此，我们第一阶段的主要目标是改善生长抑制。 效力，同时保持和/或改善先导化合物的类药特性，以便能够测试 具体来说，我们将1）使用药物化学药物 设计策略以提高体外效力、代谢稳定性和溶解度，并将在体内建立 优化 TZP 在小鼠体内的药代动力学 (PK) 曲线（包括口服生物利用度）；2) 研究其中的作用； 优先先导 TZP 的体外和体内功效，并产生对这些药物具有抗性的自发突变体 化合物可以更好地了解细菌靶标和 MoA，正如我们发现的抗分枝杆菌。 我们的 TZP 轨道的效力及其增强 INH 的能力，我们将继续抽查这个二级 在我们的 TZP 优化过程中，我们希望能够确定一个 先进的先导 TZP 化合物在急性结核小鼠模型中显示出功效，这可能会进一步 该药物是在未来的 II 期 SBIR 项目中开发的，作为治疗 DS 结核病和耐药结核病的联合疗法的一部分。