Design, Syntheses and Studies of Novel Antituberculosis Agents

新型抗结核药物的设计、合成与研究

• 批准号: 10113138
• 负责人: MARVIN J MILLER
• 金额: $ 59.07万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10113138
• 关键词: Amides; Antitubercular Agents; Award; Cessation of life; Clinical; Collaborations; Communities; Complex; Cytochromes; Development; Disease; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Evaluation; Genus Mycobacterium; Goals; Growth; Human; Hypoxia; In Vitro; Infection; Instruction; Lead; Legal patent; Lung; Maximum Tolerated Dose; Metabolism; Microbe; Mitochondria; Molecular Weight; Monkeys; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Nutrient; Oxidases; Oxidative Phosphorylation; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Preparation; Primates; Property; Publishing; Research; Rifampin; Risk; Sampling; Series; Solubility; Thiazoles; Toxic effect; Tuberculosis; animal efficacy; antibiotic tolerance; aqueous; bactericide; clinical candidate; comparative efficacy; cost effective; cost effectiveness; design; drug development; effective therapy; experience; extensive drug resistance; global health; in vivo; inhibitor/antagonist; isoniazid; laboratory experience; mouse model; nanomolar; novel; novel therapeutics; pathogen; pre-clinical; pyridine; resistant strain; respiratory; scaffold; small molecule inhibitor; tuberculosis drugs; tuberculosis treatment

Tuberculosis (TB) is a highly contagious airborne pathogen that infects > 2 billion people, of whom an estimated 1.5 million people per year are killed by the disease. The global spread of multi-drug resistant (MDR), extensively-drug resistant (XDR), and totally drug resistant (TDR) strains of tuberculosis emphasizes the great need for new effective treatments. This renewal/Merit Award application capitalizes on the discovery of hits against two critical targets in Mycobacterium tubersuolsis – the imidazo[1,2-a]pyridine-3-carboxamides and the imidazo[2,1-b]pyridine-5- carboxamides that target QcrB and novel scaffolds that target complimentary BD oxidase – and seeks to advance these to potential TB treatments. As the first to patent, prolifically publish, and propose the mechanism of action for the imidazo[1,2-a]pyridine-3-carboxamide (IAPC) series, we are the most experienced group to continue development of this series through primate evaluation in preparation for clinical (human) studies. Additionally, we have disclosed the impressive in vitro properties of imidazo[2,1-b]thiazole 5-carboxamide (IT) series a new promising, rationally designed, scaffold we will continue to develop. This new class has low nanomolar antiTB activity against H37Rv, multidrug resistant (MDR) and extreme drug resistant (XDR) Mtb as well as good in vitro metabolism and in vivo exposure with greater lung to plasma ratios. Most recently, we have discovered a small molecule inhibitor of cytochrome bd oxidase in Mtb. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from the preclinical imidazopyridine (Q203)-induced bacterial death, highlighting the attractiveness of the bd- type terminal oxidase for drug development. Combination of our QcrB and bd oxidase inhibitor is bactericidal against replicating, nutrient-starved and hypoxic antibiotic-tolerant mycobacteria and showed increased efficacy in a mouse model of infection. These results indicate that further complementary development of a compound scaffold inhibiting the cytochrome bd oxidase will enhance the value of a drug combination targeting oxidative phosphorylation for treatment of tuberculosis. Furthermore, all of these heterocyclic scaffolds (IAPC, IT and bd oxidase inhibitor) can be prepared in bulk (50 – 100 g) inexpensively and, from these penultimate intermediates, lead compounds with animal efficacy can be prepared in just one synthetic step (amide bond formation or nucleophilic aromatic substitution) and in multi-gram quantities (>15 g). Through our extensive collaborations, we will evaluate all samples and combinations for antiTB activity. We will also perform related studies, including microbe selectivity, gross toxicity particularly looking to avoid mitochondrial toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD), mice and/or monkey efficacy and mode of action studies of any new compounds with promising activity and physicochemical attributes including metabolite identification. Our criteria for a clinical candidate are: selective nanomolar potency against H37Rv and drug resistant Mtb, in vivo efficacy comparable to first line drugs isoniazid and rifampicin (at a dose <100 mg/kg), low toxicity (at least 10x over effective dose), minimal drug-drug interactions, good aqueous solubility (>100 g/mL) and synthetic simplicity/cost effectiveness. A highly qualified team of coworkers and collaborators from experienced laboratories has been assembled to accomplish the overarching goal of providing the TB-research and biomedical communities a promising new anti-tb drug treatment as well as validated new drug targtes (respiratory bc1 complex bd oxidase of Mtb). RELEVANCE (See instructions): Tuberculosis (TB) is a serious global health risk that infects more than 2,000,000,000 people worldwide and causes a death every 20 seconds! The objective of this proposal is to develop cost effective anti-TB agents. The focus is on studies of new small molecular weight compounds that are easily synthesized, non-toxic, and yet effective at inhibiting TB growth.

结核病(TB)是一种高度传染性的空气传播病原体，感染20亿人，其中 据估计，每年有150万人死于这种疾病。多种药物在全球的传播 耐药(MDR)、广泛耐药(XDR)和完全耐药(TDR)株 结核病强调了对新的有效治疗方法的迫切需要。本次续订/奖励 应用程序利用对分枝杆菌两个关键靶点的命中发现 结核杆菌-咪唑并[1，2-a]吡啶-3-甲酰胺和咪唑并[2，1-b]吡啶-5- 靶向QcrB的羧胺和靶向免费BD氧化酶的新型支架- 并寻求将这些推进到潜在的结核病治疗中。作为第一个获得专利、大量出版的公司， 并提出了咪唑并[1，2-a]吡啶-3-甲酰胺(IAPC)系列的作用机理， 我们是通过灵长类动物继续开发这一系列的最有经验的团队 临床(人体)研究准备工作中的评估。此外，我们还披露了令人印象深刻的 咪唑并[2，1-b]噻唑5-甲酰胺(IT)系列化合物的体外性质 设计，脚手架，我们将继续发展。这一新类别具有较低的纳米分子抗结核活性 对抗H37Rv、多药耐药(MDR)和极端耐药(XDR)结核分枝杆菌，以及良好的 体外代谢和体内暴露，肺与血浆的比率更大。最近，我们有 在Mtb中发现了一种细胞色素BD氧化酶的小分子抑制剂。功能冗余 细胞色素BCC：Aa3和细胞色素BD氧化酶之间保护结核分枝杆菌免受 临床前咪唑吡啶(Q203)诱导细菌死亡，突显BD- 用于药物开发的末端氧化物型。我们的QcrB和BD氧化酶抑制剂的组合是 对复制、营养匮乏和耐低氧抗生素的分枝杆菌和 在小鼠感染模型中显示出更高的疗效。这些结果表明，进一步 互补开发抑制细胞色素BD氧化酶的复合支架 提高以氧化磷酸化为靶点的药物组合在治疗骨肉瘤中的价值 肺结核。 此外，所有这些杂环支架(IAPC、IT和BD氧化酶抑制剂)都可以制备 散装的(50-100克)廉价，从这些倒数第二个中间体，先导化合物 只需一个合成步骤(形成酰胺键或亲核试剂)即可获得动物功效 芳香族取代)和多克量(&gt；15克)。通过我们广泛的合作， 我们将评估所有样本和组合的抗结核病活性。我们还将表演相关的 研究，包括微生物选择性，总毒性，特别是寻找避免线粒体 毒性、代谢、药代动力学(PK)、最大耐受量(MTD)、小鼠和/或猴子 任何具有良好活性的新化合物的药效和作用模式研究 包括代谢物鉴定在内的物理化学属性。我们对临床候选人的标准 有：对H37Rv和耐药结核分枝杆菌的选择性纳摩尔效力，体内疗效相当 一线药物异烟肼和利福平(剂量100 mg/kg)，低毒(至少10倍以上) 有效剂量)、最小的药物-药物相互作用、良好的水溶解性(&gt；100g/mL)和人工合成 简单性/成本效益。高素质的同事和合作者团队来自 经验丰富的实验室已经聚集起来，以实现以下首要目标 为结核病研究和生物医学界提供一种有前途的抗结核新药 治疗以及有效的新药Targates(Mtb的呼吸性Bc1复合体BD氧化酶)。 相关性(请参阅说明)： 结核病是一个严重的全球健康风险，感染了20多亿人 全世界的人，每20秒就有一人死亡！这项提议的目的是 就是开发具有成本效益的抗结核药物。重点是研究新的小 易合成、无毒、有效的分子量化合物 抑制结核病的生长。