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（由申请人提供）：在整个拉丁美洲高度流行的木马疾病是由寄生虫锥虫菌群引起的严重而令人衰弱的感染，导致严重的心肌病或巨肿。由于与当前疗法，苯甲酰唑和Nifurtimox相关的明显耐药性，毒性和低疗效，因此需要新药物。 UCSF的Sandler中心最近开发了一种新的高通量筛选（HTS）测定，以筛选化学治疗剂，以抗针对Cruzi的细胞内致病阶段的功效。为了回应NIAID RFA-09-034与产品开发的合作伙伴关系，我们建议支持UCSF的Novartis基金会基因组研究所（GNF），Sandler中心和小分子发现中心（SMDC）之间的合作，以实现这一启动性的研究目标和目标，以实现这一启动性的目标。这三个中心拥有出色的临床前药物发现计划和功能，包括广泛的化合物图书馆。我们建议利用这种新开发的Cruzi测定法进行HTS运动，以确定用于药用化学铅优化的潜在化学型。从确定的化学型中，我们将使用迭代药物化学铅优化策略选择至少两个具有铅样性能来进一步开发的化学型系列。该策略将结合复合功效和类似药物的特征（ADMET）的体外测试，并评估体内药代动力学和功效特性，以不断指导进一步的药物化学工作。我们预计，在赠款期结束时，我们将确定一到三个完全优化的候选人，具有良好的功效，药代动力学和毒性谱，以进一步转化，作为治疗chagas病的潜在药物。 项目叙述：迫切需要由克鲁齐寄生虫感染引起的新药来治疗被忽视的热带疾病chagas。对于这笔赠款，我们建议利用在UCSF开发的新型锥虫高吞吐量筛选测定法，以筛选GNF（Novartis基金会基因组研究所）提供的大型高质量图书馆，以及UCSF和GNF共同使用此屏幕的铅来制定一项完整的药物化学铅铅启动优化计划。在赠款期结束时，我们预计具有1-3个具有良好功效，药代动力学和毒性谱的全面优化的临床候选者，这些临床概念有望进行辅助研究，以准备启动人类临床试验。