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.

产品说明： 常见细菌病原体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。由于相对缺乏新抗生素的发现，尤其是那些具有新作用机制的抗生素，使耐药性问题变得更加复杂。在过去的几年里，Promiliad Bioprotima一直在开发针对二氢叶酸还原酶的新抑制剂，作为治疗病原菌，真菌和原生动物的方法。通过我们和我们的合作者的努力，主要由STTR赠款，我们发现了一类抗叶酸剂，其特征在于通过三原子炔丙基桥连接的2，4-二氨基嘧啶和联芳基结构域。这类分子是发现传染病新疗法的重要先导。目前这类化合物虽然具有针对抗生素耐药病原体的活性，但目前缺乏足够的代谢稳定性。这些化合物具有短的体内（和体外）半衰期，这使得进展到先导化合物状态有些困难。我们已经发现，通过用不可代谢的生物电子等排体取代结构的关键片段，我们可以保留针对一系列革兰氏阳性病原体的效力，同时大大提高选择性和代谢半衰期。本项目的目标是设计、合成和测定其他生物电子等排类似物，这些类似物在效力、代谢和物理性质方面表现出类似或更好的改善。我们在第一阶段申请中的目标是获得一个明确的领先候选人。第二阶段的项目将继续从这项工作，然后进行IND使能实验与提交IND申请的明确目标。