Development of a New Diamine (SQ109) 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性腹泻的主要原因，是一种新出现的耐药感染。治疗艰难梭菌感染（CDI）的抗生素药库是有限和不充分的：尽管万古霉素和甲硝唑对初始疾病有效，但它们与复发率或再感染率高有关。因此，迫切需要新的艰难梭菌药物。Sequella公司发现了一类具有新型抗菌活性的小分子乙二胺化合物。SQ109是这类化合物中的一种，目前正在进行治疗结核病的临床试验。1a期和b期研究证明了人体的安全性，二期疗效试验将于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，我们建议将该先导化合物作为优化乙二胺治疗CDI的基础。在Aim 1中，我们将(a)合成220-240个基于SQ109结构的乙二胺化合物，(b)通过一系列实验评估它们对艰难梭菌的体外活性（测定最低抑制浓度，MIC）、哺乳动物细胞毒性和阻断艰难梭菌毒素释放的能力。基于构效关系，我们将合成并评价其他化合物。在Aim 2中，在Aim 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，对肠道菌群的活性（以评估特异性）。最有希望的化合物也将进行预测吸收、分布、代谢、排泄和毒性研究。同样，我们可以根据本目的获得的SAR数据合成和评价其他化合物。在Aim 3中，将对5种最佳化合物进行更深入的一系列研究，包括额外的体内功效研究、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频率的测定。最后，在Aim 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/药效学测试和剂量发现毒性研究。在这项拨款结束时，我们的目标是确定治疗CDI的最佳乙二胺。我们将完成开展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，用于CDI新药候选的临床测试。

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.