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，感染了超过20亿人，其中估计 1.5每年有100万人死于这种疾病。多药耐药（MDR）的全球蔓延，广泛- 耐药（XDR）和完全耐药（TDR）结核菌株的出现，强调了对新药物的巨大需求。 有效的治疗。这个更新重新提交申请利用了两个热门系列的发现 - 咪唑并[1，2-a]吡啶-3-甲酰胺和咪唑并[2，1-B]噻唑-5-甲酰胺-和 寻求将这些技术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 咪唑并[1，2-a]吡啶-3-甲酰胺（IAPC）系列的作用机制，我们是最 经验丰富的小组通过灵长类动物评价继续开发该系列，为临床试验做准备。 （人类）研究。最近，我们用一种ND-10885在灵长类动物中评价了两种先导化合物的PK 显示出极大的暴露（>20小时的药物水平高于MIC）。此外，我们还披露了 咪唑并[2，1-B]噻唑5-甲酰胺（IT）系列的体外性能令人印象深刻， 设计，脚手架，我们将在这个建议。这种新的类别具有低纳摩尔的抗TB活性， H37 Rv、多药耐药（MDR）和极端耐药（XDR）Mtb以及良好的体外代谢 和体内暴露具有更大的肺与血浆比率。此外，这两种杂环支架（IAPC） 和IT）可以廉价地大量制备（50 - 100 g），并且由这些倒数第二中间体， 具有动物功效的化合物可以仅在一个合成步骤（酰胺键形成）中制备， 克量（>15 g）。通过我们广泛的合作，我们将评估所有样本的抗结核活性 [包括Mtb的MDR和XDR菌株]。我们还将进行相关研究，包括微生物选择性， 毒性，特别是希望避免线粒体毒性、代谢、药代动力学（PK）、最大 耐受剂量（MTD）、小鼠和/或猴功效和任何新化合物的作用模式研究， 有前景的活性和理化属性，包括代谢物鉴定。我们的临床标准 候选物是：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（至少超过有效剂量10倍）， 最小的药物相互作用，良好的水溶性（>100 µg/mL）和合成简单/成本效益。 来自学术界经验丰富的实验室的高素质的同事和合作者团队， 行业和国家卫生研究院已经组装，以实现提供结核病的总体目标， 研究和生物医学界40年来的第二种新药治疗，以及一种经过验证的 新的药物靶点（结核分枝杆菌呼吸道bc 1复合物）。

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).