Advancing lead dipiperidine compound into preclinical development

推进二哌啶先导化合物进入临床前开发

• 批准号: 7612508
• 负责人: MARINA N PROTOPOPOVA
• 金额: $ 30.51万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-03 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612508
• 关键词: Accounting; Address; Adverse effects; Antibiotics; Antitubercular Agents; Biological Availability; Canis familiaris; Cause of Death; Cell Wall; Cessation of life; Chronic; Clinical; Clinical Trials; Communicable Diseases; Critical Pathways; Data; Development; Diamines; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Epidemic; Evaluation; Extreme drug resistant tuberculosis; Funding; HIV Seropositivity; Human; In Vitro; Infection; Lead; Liver Microsomes; Maximum Tolerated Dose; Microbiology; Monkeys; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Oral Administration; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Plasma Proteins; Population; Preclinical Testing; Property; Protein Binding; Public Health; Rattus; Reporting; Research Design; Resistance; Rifampin; Series; Small Business Innovation Research Grant; Techniques; Therapeutic; Time; Toxic effect; Treatment Protocols; Tuberculosis; Work; World Health Organization; antimicrobial; attributable mortality; combat; drug candidate; improved; in vitro activity; in vivo; isoniazid; latent infection; mouse model; pre-clinical; preclinical study; programs; public health relevance; resistant strain; small molecule; stem; tuberculosis drugs

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.

描述（由申请人提供）：在我们之前的工作中，我们鉴定了一系列有效的细胞壁抑制二哌啶，它们在结构上与任何现有的抗结核药物无关。经过对先导分子的抗菌活性和药物特性的广泛分析，化合物 SQ609 被选为最有前途的候选者：它具有优异的体内活性、良好的药理学特性，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。拟议的每项具体目标都将为 SQ609 作为抗结核药物的进一步开发提供决定性的数据。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 SQ609 作为新型抗结核药物的潜力。我们将在慢性结核感染小鼠模型中进行体内药效研究，以确定最有效的剂量，评估SQ609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SQ609体外对非复制性Mtb的活性，以评估SQ609治疗潜伏结核分枝杆菌的适用性。 感染;评估 SQ609 与现有抗结核药物以及 Sequella 的结核病候选药物 SQ109 组合的体外抗 Mtb 活性，以确定任何协同、拮抗或相加效应。我们将研究SQ609的药理特性：血浆和肝微粒体的稳定性评价以及SQ609的血浆蛋白结合；确定 SQ609 的药代动力学参数和静脉注射和口服给药后小鼠体内的生物利用度，以及单次给药后药物在小鼠体内的组织分布情况。公共卫生相关性：结核病 (TB) 是由单一病原体造成的人类死亡人数最多的原因，也是 HIV 阳性人群死亡的主要原因，占全球艾滋病相关死亡的 11%。如果将艾滋病毒合并感染人群中的结核病死亡算在内，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，为期六个月，由于副作用明显且长时间日常治疗不便，依从率很低（30-60%）。数十年来对现有抗生素的滥用和不良的依从性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。 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药物利福平和异烟肼具有耐药性，并且对至少两类二线药物也具有耐药性。迫切需要新的更有效的药物来缩短疗程、治疗耐药感染并遏制结核病死亡人数的上升。在我们之前的工作中，我们鉴定了一系列有效的细胞壁抑制二哌啶，它们在结构上与任何现有的抗结核药物无关。经过对先导分子的抗菌活性和药物特性的广泛分析，化合物 SQ609 被选为最有前途的候选者：它具有优异的体内活性、良好的药理学特性，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。拟议的每项具体目标都将为 SQ609 作为抗结核药物的进一步开发提供决定性的数据。拟议的研究旨在解决新结核病治疗的标准：1）提供比标准治疗方案更快、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。根据 SBIR 第一阶段资助，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，包括血浆和肝微粒体的稳定性评估、血浆蛋白结合以及基本药代动力学参数、生物利用度以及 SQ609 在静脉注射和口服给药后在小鼠体内的组织分布情况。这些具体目标的完成将为支持 SQ609 作为抗结核药物的开发提供重要数据，并为确定是否将 SQ609 推进广泛的临床前测试提供坚实的理由。