Advancing lead dipiperidine compound into preclinical development

描述（由申请人提供）：在我们以前的工作中，我们鉴定了一系列有效的细胞壁抑制二哌啶，其结构与任何现有的抗结核药物无关。在对先导化合物的抗菌活性和药物性质进行广泛分析后，选择化合物SQ 609作为最有希望的候选者：它具有优异的体内活性，有利的药理学性质，并且可以容易地大规模合成。这项SBIR第一阶段申请的总体目标是研究SQ 609的效价、药理学和潜在毒性。每一个提出的具体目标都将为进一步开发SQ 609作为抗结核药物提供决定性的数据。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SQ 609作为一种新的抗结核药物的潜力。我们将在小鼠慢性结核感染模型中进行体内疗效研究，以确定最有效剂量，评估SQ 609对药物敏感和耐药结核分枝杆菌（Mtb）临床分离株的体外活性，确定SQ 609对非复制型Mtb的体外活性，以评估SQ 609治疗潜伏感染的适用性;评估SQ 609与现有抗结核药物以及Sequella的TB候选药物SQ 109组合对抗Mtb的体外活性，以确定任何协同、拮抗或累加效应。我们将研究SQ 609的药理学性质：SQ 609在血浆和肝微粒体中的稳定性评价和血浆蛋白结合;测定SQ 609在IV和PO给药后小鼠中的药代动力学参数和生物利用度，以及单次给药后药物在小鼠中的组织分布特征。公共卫生相关性：结核病（TB）是由单一病原体引起的人类死亡人数最多的原因，也是HIV阳性者的主要死因，占全世界艾滋病相关死亡的11%。如果将结核病死亡人数包括在艾滋病毒合并感染人口中，每年有近300万人死于结核病。目前世界卫生组织（WHO）推荐的结核病治疗方案需要服用四种药物六个月，由于如此长时间的显著副作用和日常治疗的不便，其依从率令人沮丧（30-60%）。几十年来滥用现有抗生素和依从性差造成了耐药性的流行，现在威胁着全世界的结核病控制计划。在2006年初，临床医生开始报告分离出广泛耐药结核菌株（XDR-TB），其对两种最重要的一线结核药物利福平和异烟肼具有耐药性，并且还对至少两类二线药物具有耐药性。迫切需要新的更有效的药物来缩短疗程，治疗耐药感染，并阻止结核病死亡人数的上升。在我们以前的工作中，我们确定了一系列有效的细胞壁抑制二哌啶，结构上与任何现有的抗结核药物无关。在对先导化合物SQ 609的抗菌活性和药物性质进行了广泛的分析后，选择SQ 609作为最有前途的候选化合物：它具有优异的体内活性，良好的药理学性质，并且易于大规模合成。这项SBIR第一阶段申请的总体目标是研究SQ 609的效价、药理学和潜在毒性。每一个提出的具体目标都将为进一步开发SQ 609作为抗结核药物提供决定性的数据。拟议的研究旨在解决新的结核病治疗标准：1）提供比标准治疗方案更快，更有效的治愈，2）改善MDR和XDR-TB的治疗; 3）开发潜伏感染的治疗方法。在SBIR第一阶段的资助下，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SQ 609作为一种新的抗结核药物的潜力。我们将研究SQ 609的药理学特性，包括血浆和肝微粒体中的稳定性评价、血浆蛋白结合率以及基本药代动力学参数、生物利用度和IV和PO给药后SQ 609在小鼠中的组织分布特征。这些特定目的的完成将为支持SQ 609作为抗结核药物的开发提供重要数据，并为确定是否将SQ 609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.