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：常见细菌病原体之间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。由于相对缺乏发现新的抗生素，特别是那些具有新作用机制的抗生素，耐药性问题变得更加复杂。在过去的几年里，Promiliad Biophma一直在开发新的抑制剂，将二氢叶酸还原酶作为治疗病原菌、真菌和原生动物的一种方法。通过我们和我们的合作者的努力，我们发现了一类以2，4-二氨基嘧啶和通过三原子炔丙基桥连接的联芳基结构域为特征的抗叶酸盐。这类分子是发现一种新的传染病治疗方法的重要线索。目前的一类化合物，虽然有效的抗菌剂对抗生素耐药病原体具有活性，但目前缺乏足够的代谢稳定性。这些化合物在体内(和体外)的半衰期很短，这使得进展到先导化合物状态变得有些困难。我们发现，通过将结构的关键片段替换为不可代谢的生物同工酶，我们可以保持对一系列革兰氏阳性病原体的效力，同时极大地提高选择性和代谢半衰期。该项目的目标是设计、合成和测定更多在效力、新陈代谢和物理性质方面表现出类似或更好改善的生物等立体类似物。我们在这一阶段申请的目标是获得一个明确的领先候选人。在这项工作的基础上继续进行的第二阶段项目随后将进行支持IND的试验，其明确目标是提交IND申请。