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: 8444472
• 负责人: MARINA N PROTOPOPOVA
• 金额: $ 72.58万
• 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/8444472
• 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; public health relevance; 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.

描述（由申请人提供）：艰难梭菌是医院内抗生素相关性腹泻（一种新出现的耐药感染）的主要原因。用于治疗艰难梭菌感染 (CDI) 的抗生素药物是有限且不充分的：尽管万古霉素和甲硝唑对初始疾病有效，但它们与高复发或再感染率相关。因此，迫切需要针对艰难梭菌的新药。 Sequella, Inc. 发现了一类新型小分子乙二胺化合物，具有新颖的抗菌活性机制。 SQ109 是此类化合物之一，目前正处于治疗结核病 (TB) 的临床试验中。 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。除了抗结核活性外，SQ109 还具有抗艰难梭菌的体外活性，我们建议使用这种先导化合物作为优化治疗 CDI 的乙二胺的基础。在目标 1 中，我们将 (a) 基于 SQ109 结构合成 220-240 种乙二胺化合物，并 (b) 在一系列体外试验中评估它们对艰难梭菌的体外活性（确定最低抑制浓度，MIC）、哺乳动物细胞的细胞毒性以及阻止艰难梭菌毒素释放的能力。根据构效关系，我们将合成并评估其他化合物。在目标 2 中，目标 1 中确定的最有希望的 15-20 种化合物将在其他研究中进行评估，包括确定小鼠的最大耐受剂量、感染动物模型的体内功效、针对肠道菌群的活性（以评估特异性）。最有前途的化合物还将接受预测吸收、分布、代谢、排泄和毒性研究。同样，我们可以根据为此目的获得的 SAR 数据合成和评估其他化合物。在目标3中，将对5种最佳化合物进行更深入的系列研究，包括额外的体内药效研究、体内药代动力学（PK）评估、活性谱、与其他药物的协同作用以及体外耐药发生频率的测定。最后，在目标 4 中，我们将选择最佳化合物来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。在这笔资助结束时，我们的目标是确定最适合治疗 CDI 的乙二胺。我们将完成开始 IND 指导的临床前研究所需的所有研究，最终目标是向 FDA 提交 IND 申请，用于 CDI 新候选药物的临床测试。