Development of stable isosteres of dihydrofolate reductase inhibitors as antibact

作为抗菌剂的二氢叶酸还原酶抑制剂的稳定等排体的开发

• 批准号: 8591361
• 负责人: Nigel D PRIESTLEY
• 金额: $ 28.78万
• 依托单位: PROMILIAD BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591361
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Biological; Biological Assay; Clinical Trials; Communicable Diseases; Data; Development; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Enzymes; Evaluation; Event; Folate; Folic Acid Antagonists; Funding; Generations; Goals; Grant; Half-Life; In Vitro; Infection; Lead; Link; Maximum Tolerated Dose; Metabolic; Metabolism; Methods; Modeling; Pattern; Pharmaceutical Chemistry; Phase; Protozoa; Public Health; Relative (related person); Resistance; Resistance profile; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Staphylococcus aureus; Structure; Structure-Activity Relationship; Toxic effect; Trimethoprim; Work; analog; base; design; diaminopyrimidine; follow-up; fungus; improved; in vivo; infectious disease treatment; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; mouse model; novel; novel therapeutics; pathogen; pathogenic bacteria; physical property; pre-clinical; preclinical evaluation; public health relevance; research study; screening

DESCRIPTION: Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the relative lack of discovery of new antibiotics, especially those with novel mechanisms of action. Over the past several years Promiliad Biopharma has been developing new inhibitors that target the enzyme dihydrofolate reductase as a method of treatment for pathogenic bacteria, fungi and protozoa. Through our efforts and those of our collaborators, largely funded by STTR grants, we have discovered a class of antifolates characterized by a 2, 4- diaminopyrimidine and a biaryl domain linked through a three-atom propargyl bridge. This class of molecules is an important lead in the discovery of a new treatment for infectious disease. The current class of compounds, while potent antibacterial agents with activity against antibiotic resistant pathogens, currently lack sufficient metabolic stability. These compounds have short in vivo (and in vitro) half-lives which make progression to lead compound status somewhat difficult. We have found that by substituting a key fragment of the structure with a non-metabolizable bioisostere we can retain potency against a range of Gram positive pathogens while greatly improving selectivity and metabolic half-life. The goal of this project is o design, synthesize and assay additional bioisosteric analogs which display similar or better improvements in potency, metabolism and physical properties. Our goal in this Phase I application is to obtain a clear lead candidate. A Phase II project continuing from this work would then conduct IND-enabling experiments with the clear goal of filing an IND application.

描述：常见细菌病原体中的抗生素耐药性是一个严重的公共卫生问题，因为它损害了我们治疗传染病的能力。相对缺乏新抗生素的发现，尤其是那些具有新颖的作用机理的抗生素，抗药性问题更加复杂。在过去的几年中，Promiliad Biopharma一直在开发新的抑制剂，这些抑制剂将酶二氢叶酸还原酶作为致病细菌，真菌和原生动物的治疗方法。通过我们的努力和我们的合作者的努力，在很大程度上由STTR赠款资助，我们发现了一类以2、4-二氨基吡啶丁胺和通过三个原子propargyl桥连接的二氨基吡啶胺的特征。这类分子是发现一种新的传染病治疗方法的重要领导。当前的化合物类别虽然具有抗抗生素耐药性病原体活性的有效抗菌剂，但目前缺乏足够的代谢稳定性。这些化合物的体内（和体外）半衰期都短，使得进展降低了复合状态。我们发现，通过将结构的关键片段替换为非代谢生物膜源，我们可以在一系列革兰氏阳性病原体上保留效力，同时大大提高选择性和代谢半衰期。该项目的目的是O设计，合成和测定其他生物酶类似物，这些类似物在效力，代谢和物理特性方面表现出相似或更好的改善。我们在此阶段I应用程序中的目标是获得明确的铅候选人。然后，从这项工作中继续进行的II期项目将进行指定的实验，其明确的目标是提交IND应用程序。