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.

摘要 在革兰氏+ DNA聚合酶IIIC和IIIE的抑制剂中，几种化合物对多种革兰氏+DNA聚合酶具有活性。 厌氧革兰氏阳性细菌艰难梭菌（Cdiff）的菌株。这些化合物似乎具有选择性 Cdiff与其它革兰氏阳性厌氧菌和需氧菌的比较，以及先导化合物-2-（3，4-二氯苄基）- 7-（5-吗啉基戊基）鸟嘌呤或359 E-口服在保护仓鼠免受致死性Cdiff感染中具有活性。的 感兴趣的化合物口服吸收差，并且太弱而不能开发用于全身使用， 革兰氏阳性需氧菌感染。化合物359 E和类似物是叔胺，容易形成水溶性盐， 并且在体外和体内对Cdiff高度有效。鉴于梭状芽孢杆菌的流行程度越来越高 艰难梭菌相关性腹泻（CDAD），包括高毒力、毒素过度产生和/或抗生素- 随着耐药菌株的出现，对治疗这种疾病的新的选择性抗菌药物的需求正在增长。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， 在人类患者中的腹泻将产生治疗这种新兴传染病的新型、一流的药物。 本项目竞争性更新的具体目的是关注359 E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， 2、确定作用机制、选择性、抗棉曲酶谱和抗性发展 3、测定口服安全性、抗梭菌功效和仓鼠中359 E的吸收; 4、合成 筛选359 E的类似物作为备用LC化合物，并指定候选物用于开发（CD）。 一旦完成这项工作，将开始进行国家自主开发研究。这些包括：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。一旦完成所有临床前研究，目标9将包括 准备CD的IND申请，作为CDAD的口服治疗。 CDAD的发病率在美国和欧洲呈上升趋势，Cdiff是已确定的主要疾病。 感染性原因医院腹泻的患者已被管理的抗生素。 万古霉素和甲硝唑是治疗CDAD的一线疗法，但有报道称， 甲硝唑治疗后治疗失败和CDAD复发，以及疾病中心 美国疾病控制和预防中心（CDC）不鼓励在医院使用万古霉素治疗CDAD，以尽量减少 万古霉素耐药肠球菌和葡萄球菌的风险。各种治疗方法正在临床试验中， Cdiff感染的临床前开发，从直接作用的抗菌剂到疫苗， 化合物来中和Cdiff毒素。我们的II期研究结果表明， DNA聚合酶III抑制剂将是一种有效、无毒的口服治疗CDAD的药物。