Optimization of novel pyranopyridine efflux pump inhibitors

新型吡喃吡啶外排泵抑制剂的优化

• 批准号: 9011499
• 负责人: TIMOTHY J OPPERMAN
• 金额: $ 78.31万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011499
• 关键词: Affect; Affinity; Animal Model; Animal Testing; Animals; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacteria; Binding; Biochemical; Biocide; Biological Assay; Cells; Chemosensitization; Clinic; Complex; Data; Development; Dose; Drug Design; Drug Kinetics; Enterobacteriaceae; Escherichia coli; Evaluation; Evolution; Exhibits; Fluoroquinolones; Goals; Gram-Negative Bacteria; Health; In Vitro; Infection; Lead; Levaquin; Maps; Measures; Molecular; Monobactams; Multi-Drug Resistance; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Piperacillin-Tazobactam; Play; Predisposition; Process; Production; Property; Pseudomonas aeruginosa; Pump; Research; Resistance; Role; Sepsis; Series; Structure; System; Therapeutic; Toxic effect; Urinary tract; acute toxicity; analog; antimicrobial drug; base; beta-Lactams; clinical efficacy; cytotoxic; design; effective therapy; efficacy testing; efflux pump; improved; in vitro activity; in vivo; inhibitor/antagonist; mutant; novel; novel strategies; overexpression; pathogen; periplasm; preclinical study; resistance frequency; resistance mutation; resistant strain; safety testing; scaffold; scale up; three dimensional structure

 DESCRIPTION (provided by applicant): Multi-drug resistance (MDR) in Gram-negative pathogens, including the Enterobacteriaceae and Pseudomonas aeruginosa, poses a significant threat to our ability to effectively treat infections caused by these organisms. A major component in the development of the MDR phenotype in Gram-negative bacteria is overexpression of RND-type efflux pumps, which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell. Clearly, bacterial efflux pumps are an important target for developing novel antibacterial treatments that increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. In preliminary studies, we identified a novel pyranopyridine (MBX2319) that is a potent inhibitor of AcrAB-TolC, the major efflux pump of E. coli and other Enterobacteriaceae. MBX2319 enhances the activity of fluoroquinolones (FQs) and ß-lactam antibiotics against E. coli, but does not exhibit antibacterial activity alone nor is it cytotoxic.In Phase I we synthesized MBX2319 analogs and evaluated them for potency, selectivity, spectrum of activity, and in vitro ADME properties to identify compounds with improved activity and drug-like properties, and to generate a molecular activity map for this series. As a result of this research, we have identified analogs that exhibit a >20-fold increase in antibiotic potentiation and satisfy the criteria for successful completion of the Phase I milestones. The overall goal of this Phase II project is to further develop the pyranopyridine series to identify 23 in vivo validated lead compounds that are suitable for IND-enabling preclinical studies. In Phase II, we will utilize an approach that combines structure based drug design with medicinal chemistry to design and synthesize analogs with improved spectrum of activity and ADMET properties while maintaining potency against efflux by the Enterobacteriaceae. To facilitate this approach and probe the mechanism of action, we will generate a three dimensional structure of MBX2319 and analogs bound to AcrB. Analogs will be evaluated in a panel of secondary assays to prioritize compounds for efficacy and pharmacokinetic (PK) studies in animals. In addition, the data derived from these assays will inform the design of additional compounds. Through an iterative process of compound design and evaluation, we anticipate that we will identify 2-3 in vivo validated lead compounds with favorable PK and in vivo efficacy. In Phase III, these efflux pump inhibitors will be developed for use in combination with levofloxacin (LEV) or piperacillin/tazobactam (PIP/TAZ) as an adjunctive therapy for urinary tract and bloodstream infections as the first therapeutic indications for this inhibitor series. These adjunctive therapis represent a significant improvement over single agent therapies, because they will provide the following benefits: 1) increased antibiotic efficacy at lower concentrations, and 2) decreased evolution of resistance. The Specific Aims for Phase II are as follows. Aim 1. Chemically optimize the pyranopyridine series to generate lead compounds for animal safety and efficacy testing. Aim 2. Prioritize analogs by potency, spectrum, selectivity, favorable in vitro ADMET properties. Aim 3. Determine the three dimensional structure of pyranopyridines bound to AcrB and biochemical mechanism. Aim 4. Evaluate acute toxicity, pharmacokinetics, and efficacy of lead compounds in animal models.

 描述（由申请人提供）：革兰氏阴性病原体（包括肠杆菌科和铜绿假单胞菌）的多药耐药性（MDR）对我们有效治疗这些微生物引起的感染的能力构成了重大威胁。革兰氏阴性菌中MDR表型发展的主要成分是RND型外排泵的过表达，其将抗菌剂和杀生物剂从周质主动泵送到细胞外部。显然，细菌外排泵是开发新型抗菌治疗的重要目标，这种治疗可以增加现有抗生素的效力并减少MDR细菌的出现。在初步研究中，我们鉴定了一种新的吡喃吡啶（MBX 2319），它是大肠杆菌主要外排泵AcrAB-TolC的有效抑制剂。大肠杆菌和其他肠杆菌科。MBX 2319增强了氟喹诺酮类（FQs）和β-内酰胺类抗生素对大肠杆菌的活性。在第一阶段，我们合成了MBX 2319类似物，并评估了它们的效力、选择性、活性谱和体外ADME特性，以鉴定具有改善的活性和药物样特性的化合物，并生成该系列的分子活性图。作为这项研究的结果，我们已经鉴定出抗生素增效作用增加>20倍的类似物，并满足成功完成I期里程碑的标准。该II期项目的总体目标是进一步开发吡喃吡啶系列，以确定23种适用于IND临床前研究的体内验证的先导化合物。在第二阶段，我们将利用一种方法，结合基于结构的药物设计与药物化学，设计和合成类似物，改善频谱的活动和ADMET性能，同时保持对外排的肠杆菌科的效力。为了促进这种方法并探索作用机制，我们将生成MBX 2319和与AcrB结合的类似物的三维结构。类似物将在一组二级测定中进行评价，以优先考虑用于动物中的功效和药代动力学（PK）研究的化合物。此外，从这些试验中获得的数据将为其他化合物的设计提供信息。通过化合物设计和评价的迭代过程，我们预计将鉴定出2-3种体内验证的具有有利PK和体内功效的先导化合物。在III期，这些外排泵抑制剂将与左氧氟沙星（LEV）或哌拉西林/他唑巴坦（PIP/TAZ）联合使用，作为尿路和血流感染的预防性治疗，作为该抑制剂系列的首个治疗适应症。这些连续疗法代表了对单一药剂疗法的显著改进，因为它们将提供以下益处：1）在较低浓度下增加抗生素功效，和2）减少耐药性的演变。第二阶段的具体目标如下。目标1。对吡喃吡啶系列进行化学优化，以生成用于动物安全性和有效性测试的先导化合物。目标二。通过效力、光谱、选择性、有利的体外ADMET特性对类似物进行优先排序。目标3。确定了与AcrB结合的吡喃吡啶类化合物的三维结构及其生化机制。目标4。在动物模型中评价先导化合物的急性毒性、药代动力学和有效性。