Lead optimization of agents targeting multiple kinetoplastid parasites

针对多种动质体寄生虫的药物的先导优化

• 批准号: 9222315
• 负责人: MICHAEL P POLLASTRI
• 金额: $ 16万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222315
• 关键词: Address; Animal Model; Antiparasitic Agents; Binding Proteins; Biological Assay; Chagas Disease; Chemicals; Clinical Trials; Collection; Contract Services; Cutaneous; Cutaneous Leishmaniasis; Data; Data Set; Development; Development Plans; Disease; Disease model; Dose; Drug Kinetics; Evaluation; Funding; G-Protein-Coupled Receptors; Goals; Government; Growth Inhibitors; Human; In Vitro; Industry Collaboration; Infection; Infection Control; Insecta; Ion Channel; Laboratory Research; Lead; Leishmania; Leishmania donovani; Leishmania major; Leishmaniasis; Metabolic; Modeling; Mus; National Institute of Allergy and Infectious Disease; Parasite Control; Parasitemia; Parasites; Parasitic Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Plasma Proteins; Preclinical Drug Evaluation; Process; Property; Regimen; Safety; Series; Services; Solubility; Structure-Activity Relationship; Testing; TimeLine; Toxic effect; Toxicology; Translations; Trypanosoma cruzi; Visceral; Visceral Leishmaniasis; analog; base; clinical candidate; drug development; experimental study; genotoxicity; in vivo; in vivo Model; inhibitor/antagonist; mouse model; neglect; neglected tropical diseases; pathogen; physical property; pre-clinical; pre-clinical research; preclinical development; programs; scale up; targeted agent; therapeutic development

SUMMARY/ABSTRACT The development of drugs for Neglected Tropical Diseases (NTDs) suffers from a critical gap in the discovery process, wherein drugs screened in vitro rarely progress to the preclinical phase. While academic research laboratories often discover new compounds effective in vitro, development organizations are reluctant to perform the pre-clinical research until lead compounds show proven activity in appropriate animal models. We propose to fill this gap for three NTDs: cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), and Chagas disease by contributing new, high quality chemical matter to the candidate-seeking pipeline. This will be accomplished by producing compounds that are effective in the in vivo models of the diseases and that meet target-product profiles as described by the Drugs for Neglected Diseases initiative (DNDi). We have produced hundreds of compounds that have been tested against T. cruzi (n=312) and Leishmania major (n=420), and have identified 83 anti-chagasic compounds (EC50 ≤ 5 µM), 127 L. major inhibitors (EC50 ≤ 5 µM), and 53 inhibitors with potent activity against both pathogens. The key limitations of these compounds are in their metabolic and physical properties: limited solubility, high clearance, and high plasma protein binding. We also have in vitro data against only one species of Leishmania (L. major, which causes CL). To address these limitations we propose in the R21 phase of this project to prioritize the compounds and to identify key weaknesses that can be addressed by systematic medicinal chemistry in the R33 phase. The prioritization will require completion of in vitro L. donovani assays (of relevance to VL), and prioritization of compounds for mouse pharmacokinetic (PK) experiments. Once compounds with acceptable potency and PK properties are identified from the existing set of analogs, prioritized compounds will be advanced to assessment in mouse infection models of all three diseases. Those compounds that show efficacy in animal models of infection will be profiled in toxicity assays (human kinase, GPCR, ion channel activity, genotoxicity), completing a data package that will drive the later medicinal chemistry optimization program. In order to transition to the R33 phase, we will have minimally identified at least two compounds that meet the defined lead criteria for at least one pathogen assessed, with key issues identified for optimization in the R33 phase of the project. This phase of the project will be focused on lead-to-preclinical candidate medicinal chemistry optimization in order to achieve the targeted properties for further advancement. In order to accomplish these goals, we will employ a unique combination of academic, government, and industry collaborators. By the end of the R33 phase, we will deliver compounds that effect parasitological cure in animal models of Chagas disease, VL, and/or CL using the dosing paradigm and endpoints required by DNDi. With NIAID Therapeutic Development Services, we will round out the necessary data package for a candidate compound and one backup compound in order to either make a go/no-go decision for continued advancement towards clinical trials.

摘要/摘要 被忽视的热带病 (NTD) 药物的开发在发现过程中存在重大差距 过程中，体外筛选的药物很少进展到临床前阶段。在学术研究的同时 实验室经常发现体外有效的新化合物，但开发组织却不愿意执行 临床前研究，直到先导化合物在适当的动物模型中显示出经证实的活性。 我们建议填补三种 NTD 的空白：皮肤利什曼病 (CL)、内脏利什曼病 (VL)、 和南美锥虫病，为候选人寻求管道提供新的、高质量的化学物质。这 将通过生产在疾病的体内模型中有效的化合物来实现，并且 满足被忽视疾病药物倡议 (DNDi) 所描述的目标产品概况。我们有 生产了数百种化合物，并已针对克氏锥虫 (n=312) 和大利什曼原虫 (n=420) 进行了测试， 并鉴定出 83 种抗恰加斯化合物 (EC50 ≤ 5 µM)、127 种 L. 主要抑制剂 (EC50 ≤ 5 µM) 和 53 种 对两种病原体均具有有效活性的抑制剂。这些化合物的主要局限性在于它们的 代谢和物理特性：溶解度有限、清除率高、血浆蛋白结合率高。我们也 仅拥有针对一种利什曼原虫（利什曼原虫，导致 CL）的体外数据。 为了解决这些限制，我们建议在该项目的 R21 阶段优先考虑化合物和 确定 R33 阶段可以通过系统药物化学解决的关键弱点。这 优先排序将需要完成体外杜氏乳杆菌测定（与 VL 相关），并且优先排序 用于小鼠药代动力学（PK）实验的化合物。一旦化合物具有可接受的效力和 PK 从现有的类似物组中确定特性，优先化合物将被推进评估 在所有三种疾病的小鼠感染模型中。那些在动物模型中显示出功效的化合物 将在毒性测定（人激酶、GPCR、离子通道活性、遗传毒性）中分析感染情况，完成 将驱动后续药物化学优化程序的数据包。 为了过渡到 R33 相，我们将至少鉴定出两种化合物： 满足至少一种评估的病原体的既定主要标准，并确定了优化的关键问题 该项目的R33阶段。该项目的这一阶段将重点关注临床前候选药物 化学优化，以实现进一步发展的目标性能。为了实现 为了实现这些目标，我们将聘请学术界、政府和行业合作者的独特组合。由 R33 阶段结束时，我们将提供能够在恰加斯动物模型中实现寄生虫治疗的化合物 使用 DNDi 要求的剂量范例和终点来确定疾病、VL 和/或 CL。使用 NIAID 治疗 开发服务，我们将为候选化合物和一个备份提供必要的数据包 化合物，以便做出继续/不进行临床试验的决定。