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: 8499225
• 负责人: James H. McKerrow
• 金额: $ 107.67万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499225
• 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 Interactions; Drug Kinetics; Drug Targeting; 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; 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; screening; 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.

描述（由申请人提供）：恰加斯病在整个拉丁美洲非常流行，是一种由寄生虫克氏锥虫引起的严重且使人衰弱的感染，可导致严重的心肌病或巨型综合症。由于苯硝唑和硝呋莫司等现有疗法具有显着的耐药性、毒性和低疗效，因此迫切需要新药。加州大学旧金山分校桑德勒中心最近开发了一种新的高通量筛选（HTS）测定法，用于筛选化疗药物对克氏锥虫细胞内致病阶段的疗效。为了响应 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小分子发现中心 (SMDC) 之间的合作，以满足多个该倡议针对被忽视的热带病的研究目的和目标。这三个中心拥有出色的临床前药物发现项目和能力，包括广泛的化合物库。我们建议利用这种新开发的 T. cruzi 测定法开展 HTS 活动，以确定药物化学先导物优化的潜在化学型。从确定的化学型中，我们将选择至少两个具有先导物样特性的化学型系列，以便使用迭代药物化学先导物优化策略进行进一步开发。该策略将把化合物功效和类药特性（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，以持续指导进一步的药物化学工作。我们预计，在资助期结束时，我们将确定一到三种完全优化的候选药物，具有良好的功效、药代动力学和毒性特征，以便进一步转化开发为治疗南美锥虫病的潜在药物。