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: 10397517
• 负责人: MARVIN J MILLER
• 金额: $ 56.27万
• 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/10397517
• 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 resistant Mycobacteria 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; Persons; 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; isoniazid; laboratory experience; mouse model; nanomolar; novel; novel therapeutics; pathogen; pre-clinical; pyridine; rational design; 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，感染超过20亿人，其中 估计每年有150万人死于这种疾病。多种毒品的全球蔓延 耐药（MDR）、广泛耐药（XDR）和完全耐药（TDR）菌株 结核病强调了对新的有效治疗方法的巨大需求。本次续约/优异奖 该应用利用了对分枝杆菌中两个关键靶标的命中发现 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-甲酰胺 靶向QcrB的羧酰胺和靶向互补BD氧化酶的新型支架- 并寻求将其应用于潜在的结核病治疗。作为第一个获得专利，大量出版， 并提出了咪唑并[1，2-a]吡啶-3-甲酰胺（IAPC）系列的作用机制， 我们是通过灵长类动物继续开发这个系列的最有经验的团队 为临床（人体）研究做准备。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研究 设计，脚手架，我们将继续发展。这种新的类别具有低纳摩尔的抗结核活性 抗H37 Rv、多药耐药（MDR）和极端耐药（XDR）Mtb以及良好的 体外代谢和体内暴露，肺/血浆比值更大。最近，我们 在结核分枝杆菌中发现了细胞色素bd氧化酶的小分子抑制剂。功能冗余 细胞色素bcc：aa 3和细胞色素bd氧化酶之间的相互作用保护M。结核病从 临床前咪唑并吡啶（Q203）诱导的细菌死亡，突出了bd的吸引力， 型末端氧化酶用于药物开发。我们的QcrB和bd氧化酶抑制剂的组合是 对复制型、营养缺乏型和缺氧型耐缺氧分枝杆菌具有杀菌作用， 在小鼠感染模型中显示出增加的功效。这些结果表明，进一步 抑制细胞色素bd氧化酶的化合物支架的补充开发将 增强靶向氧化磷酸化的药物组合用于治疗 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 廉价地散装（50 - 100 g），并从这些倒数第二中间体中， 动物效力可以仅在一个合成步骤（酰胺键形成或亲核性）中制备 芳族取代）和多克量（>15 g）。通过我们广泛的合作， 我们将评估所有样品和组合的抗结核活性。我们还将执行相关 研究，包括微生物选择性，总毒性，特别是避免线粒体 毒性、代谢、药代动力学（PK）、最大耐受剂量（MTD）、小鼠和/或猴 任何具有前景活性的新化合物的功效和作用方式研究， 理化属性，包括代谢物鉴别。我们对临床候选人的标准 针对H37 Rv和耐药Mtb的选择性纳摩尔效力，体内效力相当 一线药物异烟肼和利福平（剂量<100 mg/kg），低毒性（至少10倍于 有效剂量），最小的药物-药物相互作用，良好的水溶性（>100 μ g/mL）和合成 简单性/成本效益。一个高素质的团队的同事和合作者， 经验丰富的实验室已经聚集在一起，以实现总体目标， 为结核病研究和生物医学界提供了一种有前途的新型抗结核药物 治疗以及经验证的新药物靶点（Mtb的呼吸道bc 1复合物bd氧化酶）。 相关性（参见说明）： 结核病（TB）是一种严重的全球健康风险，感染人数超过20亿。 每20秒就有一人死亡！本提案的目的 是开发成本效益高的抗结核药物。重点是研究新的小型 分子量的化合物，容易合成，无毒，但有效地在 抑制结核病的增长。