Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease

临床候选药物选择的线索识别：恰加斯病药物

• 批准号: 8107529
• 负责人: James H. McKerrow
• 金额: $ 116.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-08 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107529
• 关键词: Acute; Adsorption; African Trypanosomiasis; Antiparasitic Agents; Area; Automation; Basic Science; Benznidazole; Biological Assay; Biology; Biomedical Research; California; Canis familiaris; Cardiomyopathies; Cataloging; Catalogs; Cells; Chagas Disease; Characteristics; Chemistry; Chronic Disease; Clinical; Clinical Trials; Collaborations; Collection; Communicable Diseases; Cytochrome P450; Data; Dengue; Development; Disease model; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug resistance; Evaluation; Excretory function; Foundations; Freedom; Genome; Genomics; Goals; Grant; Human; In Vitro; Infection; Information Sciences; Institutes; Intellectual Property; Latin America; Lead; Leishmania donovani; Libraries; Liver Microsomes; Malaria; Medicine; Metabolism; Methodology; Metric; Molecular Structure; Mus; National Institute of Allergy and Infectious Disease; Nifurtimox; Oral; Parasites; Parasitic Diseases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Property; Rattus; Research; Resistance; Route; Running; San Francisco; Schistosomiasis; Screening Result; Screening procedure; Series; Solubility; Staging; Stream; Structure-Activity Relationship; Technology; Telemetry; Testing; Toxic effect; Toxicity Tests; Tropical Disease; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Universities; Validation; Visceral Leishmaniasis; analog; base; candidate selection; chemical stability; chemotherapeutic agent; cytotoxicity; drug discovery; drug efficacy; efficacy testing; genotoxicity; high throughput screening; human disease; in vitro Assay; in vitro testing; in vivo; lead series; meetings; member; mouse model; neglect; novel; novel therapeutics; pre-clinical; preclinical study; product development; programs; public-private partnership; resistant strain; response; scaffold; scale up; small molecule; success; toxicity characteristics; trend

DESCRIPTION (provided by applicant): Chagas' disease, highly prevalent throughout Latin America, is a serious and debilitating infection caused by the parasite Trypanosoma cruzi that results in severe cardiomyopathy or megasyndromes. Due to the significant drug resistance, toxicity and low efficacy associated with the current therapies, benznidazole and nifurtimox, new medicines are critically needed. The Sandler Center at UCSF has recently developed a new high-throughput screening (HTS) assay to screen chemotherapeutic agents for efficacy against the intracellular pathogenic stage of T. cruzi. In response to NIAID RFA-AI-09-034 partnerships with product development, we propose to support collaboration between the Genome Institute of the Novartis Foundation (GNF), the Sandler Center and the Small Molecule Discovery Center (SMDC) at UCSF to meet several of the research goals and objectives of this initiative in neglected tropical diseases. The three centers possess excellent preclinical drug discovery programs and capabilities, including extensive compound libraries. We propose to run an HTS campaign utilizing this newly developed T. cruzi assay to identify potential chemotypes for medicinal chemistry lead optimization. From chemotypes identified, we will select at least two chemotype series that possess lead-like properties for further development using an iterative medicinal chemistry lead optimization strategy. This strategy will combine in vitro testing of compound efficacy and drug-like characteristics (ADMET) with assessment of in vivo pharmacokinetic and efficacy properties to continually guide further medicinal chemistry efforts. We anticipate that at the end of the grant period we will have identified one to three fully optimized candidates with good efficacy, pharmacokinetic and toxicity profiles for further translational development as potential drugs to treat Chagas' disease. Project Narrative: New drugs to treat the neglected tropical disease Chagas', caused by infections of the Trypanosoma cruzi parasite, are urgently required. For this grant, we propose to utilize a novel Trypanosoma cruzi High Throughput Screening assay developed at UCSF to screen a large high quality library available from GNF (Genomic Institute of the Novartis Foundation), and jointly UCSF and GNF will use leads from this screen to embark on a full medicinal chemistry lead optimization program. At the end of the grant period we anticipate having 1-3 fully optimized clinical candidates with good efficacy, pharmacokinetic and toxicity profiles that are poised to enter into IND-enabling studies to prepare for initiating human clinical trials.

描述(申请人提供)：恰加斯病，在整个拉丁美洲非常流行，是一种由克氏锥虫寄生虫引起的严重和衰弱的感染，导致严重的心肌病或巨大综合征。由于苯硝唑和硝呋莫司的耐药性大、毒性大、疗效低，迫切需要新的药物。加州大学旧金山分校的桑德勒中心最近开发了一种新的高通量筛选(HTS)试验，以筛选对抗克氏毛滴虫细胞内致病阶段的化疗药物。为了回应NIAID RFA-AI-09-034与产品开发的合作伙伴关系，我们建议支持诺华基金会基因组研究所(GNF)、桑德勒中心和加州大学旧金山分校的小分子发现中心(SMDC)之间的合作，以实现这一倡议在被忽视的热带疾病方面的几个研究目标和目的。这三个中心拥有出色的临床前药物发现计划和能力，包括广泛的化合物图书馆。我们建议利用这一新开发的克氏锥虫试验开展HTS活动，以确定用于药物化学线索优化的潜在化学类型。从已确定的化学类型中，我们将选择至少两个具有类似铅特性的化学类型系列，以使用迭代药物化学线索优化策略进行进一步开发。这一战略将把化合物功效和类药物特性(ADMET)的体外测试与体内药代动力学和功效特性的评估结合起来，继续指导进一步的药物化学努力。我们预计，在授权期结束时，我们将确定一到三个完全优化的候选药物，这些候选药物具有良好的疗效、药代动力学和毒性特征，可以进一步进行翻译开发，作为治疗恰加氏病的潜在药物。 项目简介：迫切需要治疗由克氏锥虫寄生虫感染引起的被忽视的热带病查加斯病的新药。对于这笔赠款，我们建议利用加州大学旧金山分校开发的一种新型克氏锥虫高通量筛选试验来筛选可从GNF(诺华基金会基因组研究所)获得的大型高质量文库，并将联合UCSF和GNF使用来自该筛选的线索来启动全面的药物化学线索优化计划。在授权期结束时，我们预计将有1-3名完全优化的候选临床药物，具有良好的疗效、药代动力学和毒性特征，准备进入IND-Enabling研究，为启动人类临床试验做准备。