Preclinical development of a novel antibacterial for Clostridium difficile diseas

一种针对艰难梭菌疾病的新型抗菌药物的临床前开发

• 批准号: 8230714
• 负责人: George E Wright
• 金额: $ 141.55万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230714
• 关键词: ADME Study; Aerobic; Aerobic Bacteria; Aftercare; Anaerobic Bacteria; Analytical Toxicology; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial DNA; Bifidobacterium; Cause of Death; Centers for Disease Control and Prevention (U.S.); Chemistry; Clinical Trials; Clostridium difficile; Communicable Diseases; DNA Polymerase III; DNA Polymerase Inhibitor; DNA-Directed DNA Polymerase; Development; Diarrhea; Disease; Emerging Communicable Diseases; Enterococcus; Europe; Follow-Up Studies; Genus staphylococcus; Growth; Guanine; Hamsters; Hospitals; Human; In Vitro; Incidence; Infection; Intestines; Investigational New Drug Application; Lactobacillus; Lead; Metronidazole; Modeling; Oral; Oral Administration; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Practice Guidelines; Preparation; Prevalence; Process; Recurrence; Reporting; Resistance development; Risk; Safety; Salts; Toxicokinetics; Toxicology; Toxin; Treatment Failure; United States; Vaccines; Vancomycin; Vancomycin resistant enterococcus; Virulent; Water; absorption; analog; cGMP production; disorder prevention; genotoxicity; in vivo; inhibitor/antagonist; interest; novel; phase 2 study; pre-clinical; preclinical study; prevent; resistant strain; scale up; small molecule; tertiary amine

ABSTRACT Among inhibitors of Gram+ DNA polymerases IIIC and IIIE, several compounds are active against multiple strains of the anaerobic Gram+ bacterium Clostridium difficile (Cdiff). The compounds appear to be selective for Cdiff compared with other Gram+ anaerobes and aerobes, and a lead compound - 2-(3,4-dichlorobenzyl)- 7-(5-morpholinylpentyl)guanine or 359E - is active orally in protecting hamsters from lethal Cdiff infection. The compounds of interest are poorly absorbed orally and too weak to be developed for systemic use against Gram+ aerobe infections. Compound 359E and analogs are tertiary amines, readily form water soluble salts, and are highly effective against Cdiff in vitro and in vivo. Given the increasing prevalence of Clostridium difficile-associated diarrhea (CDAD), including that from highly virulent, toxin-overproducing and/or antibiotic- resistant strains, the need for new and selective antibacterials to treat this disease is growing. Our phase II results strongly suggest that development of the lead compound or an alternative as an oral treatment for Cdiff diarrhea in human patients will result in a novel, first in class drug to treat this emerging infectious disease. The specific aims of the competing renewal of this project are focused on preclinical development of 359E or a closely related lead compound (LC). The aims are to: 1, scale up and begin process development for 359E; 2, determine the mechanism of action, selectivity, anticlostridial spectrum, and resistance development of 359E; 3, determine oral safety, anti-clostridial efficacy, and absorption of 359E in the hamster; 4, synthesize and screen analogs of 359E as backup LC compounds, and designate a candidate for development (CD). Once this has occurred, IND-enabling studies will commence. These include: 5, in vitro ADME studies; 6, preclincal analytical, toxicology and toxicokinetic studies; 7, safety pharmacology and genotoxicity studies; 8, cGMP production of the CD. Once all preclinical studies have been completed, aim 9 will encompass preparation an IND application for the CD as oral treatment for CDAD. Incidence of CDAD is on the rise in the United States and Europe, and Cdiff is the major identified infectious cause of nosocomial diarrhea in patients to whom antibiotics had been previously administered. Vancomycin and metronidazole are first-line therapy for treatment of CDAD, but there have been reports of treatment failure and CDAD recurrence after treatment with metronidazole, and the Centers for Disease Control and Prevention (CDC) has discouraged vancomycin for treatment of CDAD in hospitals to minimize the risk of vancomycin-resistant enterococci and staphylococci. Various treatments are in clinical trials and preclinical development for Cdiff infections, ranging from direct-acting antibacterials to vaccines and compounds to neutralize Cdiff toxins. The results of our phase II studies indicated the strong likelihood that a DNA polymerase III inhibitor will be an effective and non-toxic oral treatment of CDAD.

抽象的 在革兰氏+ DNA聚合酶IIIC和IIII的抑制剂中，几种化合物具有活性 厌氧革兰氏+细菌艰难梭菌（CDIFF）的菌株。这些化合物似乎是选择性的 CDIFF与其他革兰氏+厌氧菌和清氧虫和铅化合物-2-（3,4-二氯苯基） - 7-（5-多酚烯基戊基）鸟嘌呤或359E-正在口头保护仓鼠免受致命CDIFF感染的侵害。这 感兴趣的化合物的口服吸收不佳，太薄弱了，无法进行全身使用 革兰氏+可吸收的感染。化合物359E和类似物是三级胺，很容易形成水溶性盐， 并且在体外和体内对CDIFF非常有效。考虑到梭状芽胞杆菌的患病率增加 艰难核心相关的腹泻（CDAD），包括高毒，超过毒素的产生和/或抗生素 - 抗性菌株，需要新的和选择性抗菌治疗这种疾病的菌株正在增长。我们的II期 结果强烈表明，铅化合物或替代品作为CDIFF的口服处理 人类患者的腹泻将导致一种小说，首先是类药物治疗这种新兴的传染病。 该项目竞争更新的具体目的是重点介绍359E的临床前开发 或密切相关的铅化合物（LC）。目的是：1，扩大规模并开始流程开发 359e; 2，确定作用机理，选择性，抗腹膜光谱和抗性发展 359e; 3，确定口服安全性，抗颈效力和仓鼠中359E的吸收； 4，合成 和359E作为备用LC化合物的屏幕类似物，并指定了开发候选者（CD）。 一旦发生这种情况，就会开始研究。其中包括：5，体外ADME研究； 6，， 闭内分析，毒理学和毒理学研究； 7，安全药理学和遗传毒性研究； 8， CD的CGMP产生。一旦所有临床前研究完成，AIM 9都将包含 准备CD的IND应用作为CDAD的口服处理。 美国和欧洲的CDAD发病率正在上升，CDIFF是主要的确定 以前曾施用抗生素的患者的医院腹泻的传染性原因。 万古霉素和甲硝唑是CDAD治疗的一线疗法，但有报道称 治疗失败和用甲硝唑治疗后的CDAD复发和疾病中心 控制与预防（CDC）劝阻万古霉素治疗医院的CDAD，以最大程度地减少 万古霉素抗肠球菌和葡萄球菌的风险。临床试验中有各种治疗方法 CDIFF感染的临床前开发，从直接作用抗菌物质到疫苗和 化合物中和CDIFF毒素。我们第二阶段研究的结果表明 DNA聚合酶III抑制剂将是CDAD的有效且无毒的口服治疗。