Development of a New Diamine (SQ109) for the Treatment of C. difficile Infection

开发用于治疗艰难梭菌感染的新型二胺 (SQ109)

• 批准号: 8110402
• 负责人: MARINA N PROTOPOPOVA
• 金额: $ 73.09万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110402
• 关键词: Animal Model; Anti-Bacterial Agents; Antibiotics; Antitubercular Agents; Biological Assay; Clinical Treatment; Clinical Trials; Clostridium difficile; Data; Development; Diamines; Diarrhea; Disease; Dose; Drug Kinetics; Drug resistance; Ethylenediamines; Evaluation; Excretory function; Foundations; Frequencies; Goals; Grant; Hospitals; Human; In Vitro; Infection; Intestines; Lead; Mammalian Cell; Maximum Tolerated Dose; Metabolism; Metronidazole; Minimum Inhibitory Concentration measurement; Mus; Pharmaceutical Preparations; Pharmacodynamics; Phase; Relapse; Resistance development; Safety; Series; Specificity; Structure; Structure-Activity Relationship; Testing; Toxic effect; Toxin; Tuberculosis; Vancomycin; absorption; base; cytotoxicity; drug candidate; efficacy trial; falls; in vitro activity; in vivo; microbiome; novel; preclinical study; research clinical testing; small molecule

DESCRIPTION (provided by applicant): Clostridium difficile is the major cause of nosocomial, antibiotic-associated diarrhea, an emerging drug- resistant infection. The antibiotic armamentarium for treating C. difficile infection (CDI) is limited and inadequate: although vancomycin and metronidazole are effective for initial disease, they are associated with high rates of relapse or re-infection. As a result, new drugs for C. difficile are desperately needed. Sequella, Inc. discovered a new class of small molecule ethylenediamine compounds with a novel mechanism of antibacterial activity. SQ109, one of the compounds of this class, is in clinical trials for treatment of tuberculosis (TB). Phase 1a and b studies demonstrated safety in humans, and Phase 2 efficacy trials will begin in fall 2010. In addition to anti-TB activity, SQ109 has in vitro activity against C. difficile, and we propose to use this lead compound as a foundation to the optimization of an ethylenediamine(s) for treatment of CDI. In Aim 1, we will (a) synthesize 220-240 ethylenediamine compounds based on SQ109 structure and (b) evaluate them in a series of assays for in vitro activity against C. difficile (determination of the Minimum Inhibitory Concentration, MIC), mammalian cell cytotoxicity, and ability to block C. difficile toxin release. Based on structure-activity relationships, we will synthesize and evaluate additional compounds. In Aim 2, the most promising 15-20 compounds identified in Aim 1 will be evaluated in additional studies, including determination of the maximum tolerated dose in mice, in vivo efficacy in animal models of infection, activity against intestinal flora (to evaluate specificity). The most promising compounds will also undergo predictive Absorption, Distribution, Metabolism, Excretion, and Toxicity studies. Again, we may synthesize and evaluate additional compounds based on SAR data obtained in this aim. In Aim 3, a more in-depth series of studies will be implemented for the 5 best compounds, which include additional in vivo efficacy studies, in vivo pharmacokinetic (PK) evaluations, spectrum of activity, synergy with other drugs, and determination of the frequency of resistance development in vitro. Finally, in Aim 4, we will select the best compound on which to perform additional in vivo studies, evaluate drug candidate effects on the microbiome, and perform PK/pharmacodynamic testing and dose-finding toxicity studies. At the conclusion of this grant, our goal is to have identified the ethylenediamine that is best-in-class for the treatment of CDI. We will have performed all studies necessary to commence IND-directed preclinical studies, with the ultimate goal of filing an IND with the FDA for the clinical testing of a new drug candidate for CDI. PUBLIC HEALTH RELEVANCE: Clostridium difficile is the major cause of hospital-based, antibiotic-associated diarrhea, an emerging drug-resistant infection. The antibiotics for treating C. difficile infection are limited and inadequate, and new drugs for C. difficile are desperately needed. We have identified a new class of antibiotics, and propose to optimize them for the treatment of C. difficile infection.

描述（由申请人提供）：艰难梭菌是医院内抗生素相关腹泻（一种新出现的耐药感染）的主要原因。治疗C.艰难梭菌感染（CDI）是有限的和不充分的：虽然万古霉素和甲硝唑是有效的初始疾病，他们与高复发率或再感染。因此，新的药物C。困难是迫切需要的。Sequella，Inc.发现了一类新的小分子乙二胺类化合物，具有新的抗菌活性机制。SQ 109是这类化合物之一，正在进行治疗结核病（TB）的临床试验。1a期和B期研究证明了对人体的安全性，2期疗效试验将于2010年秋季开始。除了抗TB活性外，SQ 109还具有抗C. difficile，并且我们建议使用这种先导化合物作为优化用于治疗CDI的乙二胺的基础。在目标1中，我们将（a）合成220-240个基于SQ 109结构的乙二胺化合物，并（B）在一系列体外抗C.艰难梭菌（测定最小抑制浓度，MIC）、哺乳动物细胞的细胞毒性和阻断C.艰难梭菌毒素释放基于结构-活性关系，我们将合成和评估其他化合物。在目标2中，将在其他研究中评价目标1中确定的最有希望的15-20种化合物，包括确定小鼠中的最大耐受剂量、动物感染模型中的体内疗效、对肠道植物群的活性（以评价特异性）。最有前途的化合物还将进行预测性吸收、分布、代谢、排泄和毒性研究。同样，我们可以合成和评估额外的化合物的基础上获得的SAR数据在这个目标。在目标3中，将对5种最佳化合物进行更深入的一系列研究，其中包括额外的体内疗效研究、体内药代动力学（PK）评价、活性谱、与其他药物的协同作用以及体外耐药性发生频率的测定。最后，在目标4中，我们将选择最佳化合物进行额外的体内研究，评估候选药物对微生物组的影响，并进行PK/药效学测试和剂量探索毒性研究。在这项资助结束时，我们的目标是确定乙二胺是治疗CDI的最佳药物。我们将进行所有必要的研究，以开始IND指导的临床前研究，最终目标是向FDA提交IND，用于CDI新药候选药物的临床试验。 公共卫生相关性：艰难梭菌是医院为基础的，与疟疾相关的腹泻，一种新出现的耐药感染的主要原因。治疗C.艰难梭菌感染是有限的和不充分的，和新的药物C。困难是迫切需要的。我们已经确定了一类新的抗生素，并建议优化它们来治疗C。艰难感染