Narrow-spectrum Agents Acting against Helicobacter pylori

描述(申请人提供)：这个项目的目标是开发一种针对幽门螺杆菌的治疗作用，幽门螺杆菌是消化性溃疡和胃癌的病原体。大约所有其他人都携带这种病原体，据估计，美国每年有50万例活动性感染病例。目前使用的三联疗法是质子泵抑制剂和广谱抗菌药的组合，通常是阿莫西林和克拉霉素。最近一项对临床数据的荟萃分析显示，治疗失败率为22%。据估计，70%的失败是由于抗生素耐药性。考虑到病例总数，治疗失败率非常高，幽门螺杆菌正在成为最重要的耐药病原体之一，对新的治疗方法的需求仍有相当大的未得到满足。发现一种新的治疗方法的障碍是巨大的--最后一类针对革兰氏阴性菌的抗生素--氟喹诺酮类--是40年前引入的。然而，我们认为开发一种抗幽门螺杆菌的窄谱抗菌剂应该容易得多。与需要抑制同源基团的许多蛋白质的广谱相比，对作用于单个靶点的化合物的要求较少。幽门螺杆菌也有大量独特的必需蛋白，可以作为新的抗菌药的靶点。对革兰氏阴性菌的渗透性差是开发广谱化合物的另一个主要障碍，但幽门螺杆菌没有很强的渗透性屏障。这些考虑表明，新的抗H。幽门螺杆菌化合物可以在未能生产广谱抗菌剂的商业化合物库中发现。幽门螺杆菌在微需氧条件下生长，这与标准高温超导是不相容的。我们能够开发出第一个针对幽门螺杆菌的HTS，一个试点屏幕产生了大量不同的点击。HTS的一个主要问题是大量有毒和混杂的化合物。我们用一种对抗肠道共生菌的反滤网解决了这个问题。这导致了针对幽门螺杆菌的特异性线索，并且将没有副作用，如与损害肠道菌群的广谱化合物相关的腹泻。对HITS的验证产生了有效的先导，2MP，MIC和MBC为0.04g/mL，低细胞毒性，低耐药频率，合理的ADME和SAR，使其适合进一步开发。第一阶段项目将重点关闭围绕先导系列的SAR，这将为第二阶段的药物化学优化提供信息。中试筛选的结果表明，我们有一个经过验证的选择性抗H-H的发现平台。幽门螺杆菌化合物。我们将利用这一点，并将执行更大的HTS，以确定合适的备份系列。迭代药物化学优化将与第二阶段每个系列的详细验证相结合。体外验证将包括：效力、活性光谱、耐药性发展、酸稳定剂、细胞毒性、吸收、代谢稳定性和血浆结合研究。适用于动物试验的候选药物将从药物化学中脱颖而出，使用迭代设计-制造-测试周期，旨在对每个系列的微生物、药理和安全特性进行多功能优化。接下来，化合物将在幽门螺杆菌感染的小鼠模型中进行适当的口服生物利用度和有效性的体内验证。将启动行动机制研究 寻找能显示动物药效的线索。最终结果将是有效的线索，这些线索将使我们能够与一家制药公司建立合作伙伴关系，进一步进行临床前开发，从而实现临床试验和销售一种新的消化性溃疡选择性治疗药物。

DESCRIPTION (provided by applicant): The goal of this project is to develop a therapeutic acting specifically against Helicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Roughly every other person carries the pathogen, and there are an estimated 500,000 cases annually of active infection in the US. The currently-used triple therapy is a combination of a proton pump inhibitor and broad spectrum antimicrobials, usually amoxicillin and clarithromycin. A recent meta-analysis of clinical data showed that treatment failure is 22%. An estimated 70% of failures are due to antibiotic resistance. Considering the total number of cases, treatment failure is very high, and H. pylori is emerging as one of the most significant drug-resistant pathogens, and there is a considerable unmet need for novel treatments. The obstacles for discovering a new therapeutic are formidable - the last class of antibiotics acting against Gram negative species, the fluoroquinolones, was introduced 40 years ago. However, we reasoned that it should be considerably easier to develop a narrow-spectrum antimicrobial acting against H. pylori. Demands on a compound acting against a single target are less as compared to a broad- spectrum which needs to inhibit many proteins of an orthologous group. H. pylori also have a large number of unique essential proteins which could serve as targets for new antimicrobials. Poor permeability into Gram negative bacteria is another major obstacle for developing broad-spectrum compounds, but H. pylori do not have a strong permeability barrier. These considerations suggest that novel anti-H. Pylori compounds could be discovered in an HTS of commercial compounds libraries that failed to produce broad-spectrum antimicrobials. H. pylori grow under microaerophilic conditions, which are incompatible with standard HTS. We were able to develop a first HTS against H. pylori, and a pilot screen produced a large number of diverse hits. A major problem in HTS is a large number of toxic and promiscuous compounds. We solved this problem with a counter-screen against gut symbionts. This resulted in leads that are specific against H. pylori and will be free of side-effects such as diarrhea associated with broad-spectrum compounds that harm the gut flora. Validation of the hits resulted in a potent lead, 2MP, with an MIC and MBC of 0.04 ¿g/mL, low cytotoxicity, low resistance frequency, reasonable ADME, and an SAR, making it suitable for further development. The Phase I project will focus on closing SAR around the lead series, which will inform medicinal chemistry optimization in Phase II. Results from the pilot screen suggest that we have a validated discovery platform for selective anti-H. pylori compounds. We will take advantage of this, and will perform a larger HTS in order to identify a suitable back- up series. Iterative medicinal chemistry optimization will be combined with detailed validation of each series in Phase II. in vitro validation will include: potency, spectrum of activity, resistance development, acid stabilit, cytotoxicity, absorption, metabolic stability and plasma binding studies. Candidates suitable for animal testing will emerge from medicinal chemistry using iterative design-make-test cycles aimed at multifunctional optimization of the microbiological, pharmacologic and safety properties of each series. Next, compounds will undergo in vivo validation for suitable oral bioavailability and efficacy in a mouse model of H. pylori infection. Mechanism of action studies will be initiated for leads that exhibit animal efficacy. The end result will be validated leads that will enable us o enter into a partnership with a Pharmaceutical Company for further preclinical development leading towards and IND, clinical trials, marketing a sales of a new selective therapeutic for peptic ulcer.