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: 8044832
• 负责人: George E Wright
• 金额: $ 93.55万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044832
• 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 IIIE 的抑制剂中，有几种化合物对多种酶具有活性。 厌氧革兰氏阳性细菌艰难梭菌 (Cdiff) 菌株。这些化合物似乎具有选择性 对于 Cdiff 与其他革兰氏+厌氧菌和需氧菌以及先导化合物 - 2-(3,4-二氯苄基)- 的比较 7-(5-吗啉基戊基)鸟嘌呤或 359E - 口服可有效保护仓鼠免受致命的 Cdiff 感染。这 感兴趣的化合物口服吸收很差，而且太弱，无法开发用于全身治疗 革兰氏+需氧菌感染。化合物359E和类似物是叔胺，容易形成水溶性盐， 在体外和体内均对 Cdiff 非常有效。鉴于梭状芽胞杆菌的患病率不断增加 艰难梭菌相关性腹泻 (CDAD)，包括由高毒力、毒素过量和/或抗生素引起的腹泻 由于耐药菌株的存在，对治疗这种疾病的新型选择性抗菌药物的需求不断增长。我们的第二阶段 结果强烈表明，开发先导化合物或替代品作为 Cdiff 的口服治疗方法 人类患者腹泻将产生一种新型的、一流的药物来治疗这种新出现的传染病。 该项目竞争更新的具体目标集中在359E的临床前开发 或密切相关的先导化合物 (LC)。目标是： 1、扩大规模并开始工艺开发 359E； 2、确定作用机制、选择性、抗梭菌谱和耐药性发展 359E； 3、确定359E的口服安全性、抗梭菌功效以及仓鼠体内的吸收情况； 4、合成 并筛选 359E 的类似物作为备用 LC 化合物，并指定开发候选化合物 (CD)。 一旦发生这种情况，IND 支持研究将开始。其中包括：5、体外ADME研究； 6、 临床前分析、毒理学和毒代动力学研究； 7、安全药理学和遗传毒性研究； 8、 CD 的 cGMP 生产。一旦所有临床前研究完成，目标 9 将包括 准备 CD 作为 CDAD 口服治疗的 IND 申请。 CDAD 的发病率在美国和欧洲呈上升趋势，其中 Cdiff 是已确定的主要疾病 先前使用过抗生素的患者院内腹泻的感染原因。 万古霉素和甲硝唑是治疗 CDAD 的一线药物，但有报道 甲硝唑治疗后治疗失败和 CDAD 复发，以及疾病中心 控制与预防 (CDC) 不鼓励在医院使用万古霉素治疗 CDAD，以尽量减少 耐万古霉素肠球菌和葡萄球菌的风险。多种治疗方法正在进行临床试验 Cdiff 感染的临床前开发，从直接作用的抗菌药物到疫苗和 中和 Cdiff 毒素的化合物。我们的 II 期研究结果表明，极有可能 DNA聚合酶III抑制剂将是CDAD的有效且无毒的口服治疗方法。