Benzoxaborole-based antimalarial drug discovery

基于苯并氧硼杂环戊烯的抗疟药物的发现

• 批准号: 10079937
• 负责人: Marissa Aubrey
• 金额: $ 30.05万
• 依托单位: BORAGEN INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079937
• 关键词: Advanced Development; Africa; African; Amino Acyl-tRNA Synthetases; Antimalarials; Atopic Dermatitis; Award; Bioavailable; Biological; Boron; Cells; Chemical Structure; Chemistry; Child; Cleavage And Polyadenylation Specificity Factor; Collaborations; Cryptosporidiosis; Data; Development; Drug Evaluation; Drug Exposure; Drug Interactions; Drug Kinetics; Drug resistance; Equilibrium; Erythrocytes; Evaluation; FDA approved; Homologous Gene; In Vitro; Infection; Laboratories; Laboratory Animal Models; Laboratory culture; Lead; Libraries; Life Cycle Stages; Malaria; Metabolic; Modeling; Multi-Drug Resistance; Mus; Onychomycosis; Oral; Parasites; Parasitic Diseases; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Plasmodium falciparum; Pregnant Women; Process; Property; Research; Risk; Safety; Small Business Innovation Research Grant; Structure-Activity Relationship; Toxic effect; Toxicology; Trypanosomiasis; Tuberculosis; Uganda; United States National Institutes of Health; base; cytotoxicity; design; drug development; drug discovery; experimental study; genotoxicity; human disease; in vitro activity; in vivo; in vivo evaluation; insight; leucine-tRNA; mouse model; novel; novel therapeutics; pharmacophore; pre-clinical; preclinical study; programs; resistant strain; scaffold; structural biology; success; synergism; therapy development

Modified Project Summary/Abstract Section New drugs to treat malaria, ideally with unique chemical structures and mechanisms of action, are urgently needed. Optimal antimalarials will be orally bioavailable, have extended pharmacological exposure, be safe for administration to children and pregnant women, be rapidly active against erythrocytic malaria parasites, and ideally also be active against other life cycle stages of malaria parasites. This application builds on a recent collaboration between Anacor and UCSF that established benzoxaboroles as promising new antimalarial agents. Recently, a new collaboration has developed including the original team at UCSF and former Anacor collaborators now at Boragen. We hypothesize that the proposed novel benzoxaboroles will exert potent antimalarial activity and fulfill necessary criteria to enable progression to antimalarial drug development. This Phase I SBIR application concerns the study of new classes of benzoxaboroles to establish scaffolds for detailed discovery and development in a Phase II program. Our specific aims will be: 1) to characterize structure activity relationships for antimalarial activity of benzoxaboroles, 2) to characterize the drug-like properties of benzoxaboroles with antimalarial activity, and 3) to characterize ex vivo and in vivo activity, drug interactions, and initial pharmokinetic data for advanced hits selected based on results from Aim 1 and Aim 2 studies. We anticipate that our studies will lead to the identification of multiple compounds with promising in vitro activity (Aim 1) and favorable drug-like properties (Aim 2), laying the groundwork for advancement to additional in vitro and in vivo studies in Aim 3, and then to more substantial characterization of leads in Phase II of the SBIR program.

修改项目摘要/摘要部分 迫切需要治疗疟疾的新药，最好具有独特的化学结构和作用机制。最佳的抗疟药将是口服生物可利用的，具有延长的药理学暴露，对儿童和孕妇给药是安全的，对红细胞疟疾寄生虫具有快速活性，并且理想地还对疟疾寄生虫的其他生命周期阶段具有活性。该应用建立在Anacor和UCSF之间最近的合作基础上，该合作将苯并氧杂硼杂环戊烯确定为有前途的新型抗疟疾药物。最近，一个新的合作已经开发，包括在UCSF的原始团队和前Anacor合作者现在在Boragen。我们假设，提出的新型苯并氧杂硼杂环戊烯将发挥有效的抗疟活性，并满足必要的标准，使抗疟药物的发展。这第一阶段SBIR申请关注的是新的苯并氧杂硼杂环戊烯类化合物的研究，以建立支架，用于第二阶段计划中的详细发现和开发。我们的具体目标是：1）表征苯并氧杂硼杂环戊烯抗疟活性的结构活性关系，2）表征具有抗疟活性的苯并氧杂硼杂环戊烯的药物样性质，和3）表征基于Aim 1和Aim 2研究的结果选择的高级命中的离体和体内活性、药物相互作用和初始药代动力学数据。我们预计，我们的研究将导致多种化合物的鉴定与有前途的体外活性（目标1）和有利的药物样特性（目标2），奠定了基础，为进一步在体外和体内研究目标3，然后在SBIR计划的第二阶段更实质性的特点。