Design, Syntheses and Studies of Novel Antituberculosis Agents

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，其中估计 每年有150万人死于这种疾病。多药耐药(MDR)在全球的传播，广泛- 耐药(XDR)和完全耐药(TDR)结核病菌株强调了对新的 有效的治疗方法。此续订重新提交申请利用了两部热门系列剧的发现 -咪唑并[1，2-a]吡啶-3-甲酰胺和咪唑[2，1-b]噻唑-5-甲酰胺-和 寻求将这些推进到潜在的结核病治疗中。作为第一个申请专利、大量出版和提出 对于咪唑并[1，2-a]吡啶-3-甲酰胺(IAPC)系列的作用机理，我们是最多的 经验丰富的小组通过灵长类评估继续开发该系列，为临床做准备 (人类)研究。最近，我们用一台ND-10885评估了两种先导化合物在灵长类动物身上的pk 表现出极大的暴露(&gt；20小时药物水平高于MIC)。此外，我们还披露了 咪唑并[2，1-b]噻唑5-甲酰胺(IT)系列化合物令人印象深刻的体外性能 设计，脚手架，我们将在这项建议内开发。这一新类别具有较低的纳米分子抗结核活性 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 在体内暴露时，肺与血浆的比率更大。此外，这些杂环支架(IAPC) 和IT)可以廉价地批量制备(50-100克)，并从这些倒数第二个中间体中制备铅 具有动物功效的化合物可以通过一个合成步骤(酰胺键的形成)和多个合成步骤得到. 克量(&gt；15克)。通过我们广泛的合作，我们将评估所有样本的抗结核病活性 [包括结核分枝杆菌耐多药株和XDR株]。我们还将进行相关研究，包括微生物选择性、总 毒性特别是要避免线粒体毒性，代谢，药代动力学(PK)，最大 任何新化合物的耐受量(MTD)、小鼠和/或猴子的功效和作用模式研究 前景看好的活性和物理化学属性，包括代谢物鉴定。我们的临床标准是 候选有：对H37Rv和耐药结核分枝杆菌的选择性纳米分子效力，体内疗效可比 一线药物异烟肼和利福平(剂量为100 mg/kg)，低毒(至少超过有效剂量的10倍)， 最小的药物-药物相互作用，良好的水溶解性(&gt；100微克/毫升)和合成简单性/成本效益。 一支由来自学术界经验丰富的实验室的高素质同事和合作者组成的团队， 工业界和美国国家卫生研究院已经联合起来，以实现提供结核病- 研究和生物医学社区40年来的第二种新药治疗以及经过验证的 新的药物靶点(Mtb的呼吸性Bc1复合体)。

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 resubmission application capitalizes on the discovery of two hit series – the imidazo[1,2-a]pyridine-3-carboxamides and the imidazo[2,1-b]thiazole-5-carboxamides – 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. Recently, we had the PK of two lead compounds evaluated in primates with one ND-10885 showing great exposure (>20 hours of drug levels above the MIC). Additionally, we have disclosed the impressive in vitro properties of the imidazo[2,1-b]thiazole 5-carboxamide (IT) series, a new promising, rationally designed, scaffold we will develop within this proposal. 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. Furthermore, both these heterocyclic scaffolds (IAPC and IT) 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) and in multi- gram quantities (>15 g). Through our extensive collaborations, we will evaluate all samples for antiTB activity [including MDR and XDR strains of Mtb]. 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 µg/mL) and synthetic simplicity/cost effectiveness. A highly qualified team of coworkers and collaborators from experienced laboratories from academia, industry and the NIH has been assembled to accomplish the overarching goal of providing the TB- research and biomedical communities the second new drug treatment in 40 years as well as a validated new drug target (respiratory bc1 complex of Mtb).