Lead optimization of hits identified from virtual and experimental screens of multiple industrial libraries DNDi

摘要/摘要 被忽视的热带病是发病率和死亡率的主要原因，影响超过10亿人。 世界各地的人们。考虑到营利性制药行业缺乏财政激励，几乎没有 从体外药物筛选试验到体内疗效研究的转化。我们建议取得进展。 从制药公司化合物库中确定的化合物，一直到临床前候选化合物 状态。为了实现这一目标，我们有效地参与了被忽视疾病药物倡议(DNDI 与几个合作伙伴结盟，这些合作伙伴带来了工业、药物化学、药物方面的深厚专业知识 新陈代谢和药代动力学，以及来自提供寄生虫学经验和经过验证的 有能力将治疗NTDS的药物进展到临床和更远的地方。这样的项目团队在整个NTD中都是独一无二的 药物发现的前景，是这一提议的优势所在。 我们将通过将注意力集中在化合物的设计上来实现拟议的项目目标 符合内脏利什曼病和恰加斯病的目标产品概况(TPP)。DNDI的助推器 计划通过一个独特的过程识别开始的点击，包括迭代筛选和7个测试周期 制药公司的复合库。每个库的复合成员都有很好的注释 已知的药理活性以及通过计算预测和/或实验测量的特性 (包括水溶性、代谢稳定性、体外毒理学等)，使快速鉴定 潜在的责任。这项提案重点关注Booster计划中出现的四种化学类型，即 包括大量针对利什曼原虫的有效命中。还有克氏锥虫。 R21阶段将专注于从点击到领先的优化和四种化学型的向下选择 到两个人。我们将确定在动物模型中证明概念验证疾病修改效果的化合物。 不同疾病之间的关系。此外，我们将介绍那些显示出积极影响的化合物 确定体内寄生虫血症的潜在责任，这将成为候选药物寻求的重点 R33阶段概述的化学活动。 R33阶段专注于优先化疗类型的引导到临床前候选优化。 我们在实现这一目标方面处于独特的地位，因为我们与DNDi和Celgene Corporation直接合作 贯穿整个项目。在R33阶段完成后，我们将提供两个完整的数据包 符合相应TPP的每种疾病的化合物(一个候选，一个备份)，并且将 用来证明支持IND的研究是合理的。

SUMMARY/ABSTRACT Neglected tropical diseases (NTDs) are a leading cause of morbidity and mortality, affecting over 1 billion people worldwide. Given the lack of financial incentive for the for-profit pharmaceutical industry, there is little translation seen from in vitro drug screening assays into in vivo efficacy studies. We propose to progress hit compounds, identified from pharmaceutical company compound libraries, through to pre-clinical candidate status. To achieve this, we have engaged with the Drugs for Neglected Diseases Initiative (DNDi), effectively aligning ourselves with several partners who bring deep expertise from industry, in medicinal chemistry, drug metabolism and pharmacokinetics, and from institutions that contribute parasitology experience and a proven ability to progress drugs for NTDs into the clinic and beyond. Such a project team is singular across the NTD drug discovery landscape and is a strength of this proposal. We will accomplish the proposed project goals by focusing our attention on the design of compounds which meet the Target Product Profile (TPP) for visceral leishmaniasis and Chagas disease. DNDi's Booster program identifies starting hits through a unique process, involving iterative screening and testing cycles of 7 pharmaceutical company compound libraries. The compound members of each library are well annotated with known pharmacological activity, and computationally predicted and/or experimentally measured properties (including aqueous solubility, metabolic stability, in vitro toxicology etc.), enabling the rapid identification of potential liabilities. This proposal focuses on four chemotypes that emerged from the Booster program that consist of a large number of validated hits against Leishmania spp. and Trypanosoma cruzi. The R21 phase will be focused on hit-to-lead optimization and the down-selection of the four chemotypes to two. We will identify compounds that demonstrate proof-of-concept disease-modifying effects in animal models of the respective diseases. Further, we will profile those compounds that demonstrate positive effects on parasitemia in vivo to identify potential liabilities, which will become the focus of the candidate-seeking medicinal chemistry campaign outlined in the R33 phase. The R33 phase is focused on the lead-to-preclinical candidate optimization of the prioritized chemotypes. We are uniquely placed to achieve this goal as we are collaborating directly with DNDi and Celgene Corporation throughout this project. At the completion of the R33 phase we will deliver a complete data package on two compounds for each disease (one candidate, one backup) that meets the respective TPP, and which will be used to justify IND-enabling studies.