Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease

描述（由申请人提供）：恰加斯病在拉丁美洲高度流行，是一种由克氏锥虫寄生虫引起的严重和使人衰弱的感染，可导致严重的心肌病或大症候群。由于目前的治疗方法苯并硝唑和硝呋替莫存在明显的耐药性、毒性和低疗效，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）方法来筛选化疗药物对克氏锥虫细胞内致病阶段的疗效。作为对NIAID RFA-AI-09-034产品开发伙伴关系的回应，我们建议支持诺华基金会基因组研究所（GNF）、桑德勒中心和UCSF小分子发现中心（SMDC）之间的合作，以实现该计划在被忽视的热带疾病方面的几个研究目标。这三个中心拥有优秀的临床前药物发现项目和能力，包括广泛的化合物文库。我们建议利用这种新开发的克氏t细胞试验来开展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类似铅的化学型系列，用于使用迭代药物化学先导物优化策略进行进一步开发。该策略将结合体外化合物功效和药物样特性（ADMET）测试与体内药代动力学和功效特性评估，以不断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，具有良好的疗效、药代动力学和毒性特征，用于进一步的转化开发，作为治疗恰加斯病的潜在药物。

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.