Advancing lead dipiperidine compound into preclinical development

描述（由申请人提供）：在我们之前的工作中，我们发现了一系列有效的细胞壁抑制双哌啶，它们在结构上与任何现有的抗结核药物无关。经过对先导分子的动物微生物活性和药物性质的广泛分析，我们选择了SQ609作为最有希望的候选化合物，因为它具有良好的体内活性，良好的药理性质，并且易于大规模合成。SBIR I期申请的总体目标是研究SQ609的效力、药理学和潜在毒性。每个提出的具体目标都将提供决定性的数据，以进一步开发作为抗结核药物的SQ609。我们将进行额外的体外和体内微生物学研究，以进一步表征SQ609作为一种新的抗结核药物的潜力。我们将在慢性结核感染小鼠模型中进行体内药效研究，确定最有效剂量，评估SQ609体外对药敏和耐药结核分枝杆菌（Mtb）临床分离株的活性，确定SQ609体外对非复制型结核分枝杆菌（Mtb）的活性，评估SQ609治疗潜伏感染的适用性；评估SQ609与现有抗结核药物以及Sequella的结核病候选药物SQ109联合抗Mtb的体外活性，以确定是否存在协同、拮抗或加性作用。我们将研究SQ609的药理学特性：在血浆和肝脏微粒体中的稳定性评估以及SQ609的血浆蛋白结合；测定静、PO给药后SQ609在小鼠体内的药动学参数和生物利用度，以及单次给药后SQ609在小鼠体内的组织分布。公共卫生相关性：结核病（TB）是由单一病原导致的人类死亡人数最多的原因，也是艾滋病毒阳性患者死亡的主要原因，占全世界艾滋病相关死亡人数的11%。如果将结核病死亡人数包括在艾滋病毒合并感染人群中，每年有近300万人死于结核病。目前世界卫生组织（世卫组织）推荐的结核病治疗方案要求在6个月内服用4种药物，由于严重的副作用和如此长时间每天治疗的不便，这种治疗方案的依从性很低（30-60%）。几十年来对现有抗生素的滥用和不严格的遵守造成了耐药性的流行，现在威胁着全世界的结核病控制规划。2006年初，临床医生开始报告分离出广泛耐药结核菌株（XDR-TB），这些菌株对两种最重要的一线结核病药物利福平和异烟肼耐药，并且对至少两类二线药物耐药。迫切需要新的更有效的药物来缩短治疗方案，治疗耐药感染，并遏制结核病死亡人数的上升趋势。在我们之前的工作中，我们发现了一系列有效的细胞壁抑制双哌啶，它们在结构上与任何现有的抗结核药物无关。经过对先导分子的微生物活性和药物性质的广泛分析，我们选择了SQ609作为最有希望的候选化合物，因为它具有优异的体内活性，良好的药理性质，并且易于大规模合成。SBIR I期申请的总体目标是研究SQ609的效力、药理学和潜在毒性。每个提出的具体目标都将提供决定性的数据，以进一步开发作为抗结核药物的SQ609。拟议的研究旨在解决结核病新疗法的标准：1)提供比标准治疗方案更快和更有效的治愈方法；2)改善耐多药和广泛耐药结核病的治疗；3)开发潜伏感染的治疗方法。在SBIR一期资助下，我们将进行额外的体外和体内微生物学研究，以进一步表征SQ609作为新型抗结核药物的潜力。我们将研究SQ609的药理学特性，包括在血浆和肝脏微粒体中的稳定性评估、血浆蛋白结合、基本药代动力学参数、生物利用度以及注射和PO给药后SQ609在小鼠体内的组织分布。这些具体目标的完成将为SQ609作为抗结核药物的开发提供重要的数据支持，并为确定是否将SQ609推进到广泛的临床前试验提供坚实的依据。

DESCRIPTION (provided by applicant): In our previous work we identified a series of potent cell-wall inhibiting dipiperidines that are structurally unrelated to any existing antitubercular drugs. After extensive analysis of the lead molecules for anim- icrobial activity and drug properties compound SQ609 was selected as the most promising candidate: it has excellent in vivo activity, favorable pharmacological properties, and can be readily synthesized on a large scale. The overall aim of this SBIR Phase I application is to investigate potency, pharmacology, and potential toxicity of SQ609. Each of the proposed Specific Aims will provide decisive data to proceed with further development of SQ609 as an antitubercular. We will perform additional in vitro and in vivo microbiology studies to further characterize the potential of SQ609 as a new antitubercular drug. We will conduct in vivo efficacy studies in a mouse model of chronic TB infection to determine the most efficacious dose, evaluate the in vitro activity of SQ609 against drug-susceptible and drug-resistant clinical isolates of Mycobacterium tuberculosis (Mtb), determine the activity of SQ609 against non-replicating Mtb in vitro to assess the applicability of SQ609 in treating latent infection; evaluate the in vitro activity of SQ609 against Mtb in combination with the existing antitubercular drugs, as well as Sequella's TB drug candidate SQ109, in order to determine any synergistic, antagonistic, or additive effects. We will investigate the pharmacological properties of SQ609: stability evaluation in plasma and liver microsomes and plasma protein binding of SQ609; determination of pharmacokinetic parameters of SQ609 and bioavailability in mice following both IV and PO administration, and the tissue distribution profile of the drug in mice after single dosing. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the cause of the largest number of human deaths attributable to a single etiologic agent and the leading cause of death in those who are HIV-positive, accounting for 11% of the AIDS-related deaths worldwide. If one includes TB deaths in the HIV-co-infected population, nearly 3 million people die of TB each year. The current therapeutic regimen for TB recommended by the World Health Organization (WHO) requires the administration of four drugs for six months, which has a dismal compliance rate (30-60%) as a result of significant side effects and the inconvenience of daily therapy for such a long period of time. Decades of misuse of the existing antibiotics and poor compliance created an epidemic of drug resistance that now threatens TB control programs worldwide. In early 2006, clinicians began reporting the isolation of extensively drug resistant strains of TB (XDR-TB) that are resistant to the two most important front- line TB drugs, rifampicin and isoniazid, and also resistant to at least two classes of second-line drugs. New more potent drugs are desperately needed to shorten the regimen, treat drug-resistant infection, and to stem the rising tide of TB deaths. In our previous work we identified a series of potent cell-wall inhibiting dipiperidines that are structurally unrelated to any existing antitubercular drugs. After extensive analysis of the lead molecules for animicrobial activity and drug properties compound SQ609 was selected as the most promising candidate: it has excellent in vivo activity, favorable pharmacological properties, and can be readily synthesized on a large scale. The overall aim of this SBIR Phase I application is to investigate potency, pharmacology, and potential toxicity of SQ609. Each of the proposed Specific Aims will provide decisive data to proceed with further development of SQ609 as an antitubercular. The proposed studies are designed to address the criteria for a new TB therapeutic: 1) to provide a faster and more effective cure than the standard therapeutic regimen, 2) to improve the treatment of MDR- and XDR-TB; 3) to develop treatments for latent infection. Under this SBIR Phase 1 funding we will perform additional in vitro and in vivo microbiology studies to further characterize the potential of SQ609 as a new antitubercular drug. We will investigate the pharmacological properties of SQ609 that will include stability evaluation in plasma and liver microsomes, plasma protein binding, as well as basic pharmacokinetic parameters, bioavailability, and the tissue distribution profile of SQ609 in mice following both IV and PO administration. Completion of these Specific Aims will provide vital data in support of development of SQ609 as an antitubercular and a firm rationale for determining whether or not to advance SQ609 into the extensive preclinical testing.