Antileishmanial Lead Optimization of Quinazolines

描述(申请人提供)：需要新的口服药物来治疗内脏利什曼病(VL)和皮肤利什曼病(CL)。我们的实验室发现，几种2，4-二氨基喹唑类化合物在体外具有从低微摩尔到高纳米摩尔浓度的抗利什曼活性，该系列中的一个分子(KVH14)在我们的VL小鼠模型中显示出良好的疗效。在这个项目中，我们将进行有针对性的先导优化研究，以确定可以作为治疗VL和/或CL的临床前候选化合物的喹唑啉化合物。为此，我们提出了以下目标：目标1：合成具有体内抗利什曼活性的2，4-二氨基喹唑类化合物。基于领先化合物KVH14，我们将继续进行结构-活性和结构-性质关系(SAR和SPR)研究，以增强抗利什曼活性，同时保持或改善理化性质。优化工作将主要集中在喹唑啉支架以及喹唑啉的2-，4，-5-，6-，7-和8-位的结构修饰上。目的2、2，4-二氨基喹唑类药物的抗利什曼反应评价。将进行体外和体内试验，以评估这些分子作为治疗VL和CL的候选药物的潜力。评估这些分子对细胞内的杜氏乳杆菌(引起VL)、亚马孙乳杆菌(引起新大陆CL的物种)和主要乳杆菌(引起旧大陆CL)的效力，将允许在VL(抗利什曼IC50和SI&gt；20)和CL(抗利什曼IC50和SI&gt；20)的小鼠模型中鉴定要测试的分子。严重VL的仓鼠模型也将被用来辨别在我们的小鼠VL模型中显示出显著口服疗效的喹唑啉是否应该被认为是治疗这种疾病表现的临床前候选药物。目的3.2，4-二氨基喹唑类药物的ADME/TOX分析。KVH14的代谢物鉴定和活性2，4-二氨基喹唑啉的代谢稳定性测试将使用小鼠和人的肝脏微粒体进行，以指导我们在目标1中的合成努力，以提高口服生物利用度和全身暴露。活性2，4-二氨基喹唑类化合物的几种限制发育毒性(即肝脏毒性、心脏毒性和抑制CYP3A4)将被评估，以确定化合物的优先顺序进行进一步测试。最有希望的2，4-二氨基喹唑类药物在小鼠体内的药代动力学和组织分布将被确定，以验证血浆和靶器官的暴露。 公共卫生相关性：内脏利什曼病和皮肤利什曼病是发展中国家每年影响数百万人的寄生虫病。前者在没有药物治疗的情况下通常是致命的，而后者也会影响部署的美军，会导致毁容的皮肤溃疡。由于目前用于内脏利什曼病和皮肤利什曼病的药物有几个弱点，我们正试图在我们制造的具有良好的抗利什曼特性的新化学物质的基础上发现更好的治疗这些疾病的药物。

DESCRIPTION (provided by applicant): There is a need for new oral drugs to treat visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). Our labs have discovered that several 2,4-diaminoquinazolines possess in vitro antileishmanial activity at low micromolar to high nanomolar concentrations, and one molecule in this series (KVH14) has shown promising efficacy in our murine model of VL. In this project, we will carry out focused lead optimization studies to identify quinazoline compounds that could serve as preclinical candidates for treating VL and/or CL. To this end, we propose the following aims: Aim 1: Synthesis of 2,4-Diaminoquinazolines with in vivo Antileishmanial Activity. Based on frontrunner compound KVH14, we will continue to conduct structure-activity and structure-property relationship (SAR and SPR) studies to enhance antileishmanial activity while maintaining or improving physicochemical properties. The optimization efforts will mainly focus on structural modifications on the quinazoline scaffold as well as the quinazoline's 2-, 4,- 5-, 6-, 7-, and 8-positions. Aim 2 Antileishmanial Evaluation of 2,4-Diaminoquinazolines. In vitro and in vivo assays to assess the potential of these molecules as drug candidates against both VL and CL will be conducted. Evaluation of the potency of these molecules against intracellular L. donovani (which causes VL), L. amazonensis (a species causing New World CL), and L. major (which causes Old World CL) will allow for the identification of molecules to be tested in murine models of VL (antileishmanial IC50 < 0.5 ¿M and SI > 20) and CL (antileishmanial IC50 < 2 ¿M and SI > 20). A hamster model of severe VL will also be used to discern whether a quinazoline showing outstanding oral efficacy in our murine VL model should be considered as a preclinical candidate for treating this manifestation of the disease. Aim 3. ADME/Tox Profiling of 2,4-Diaminoquinazolines. Metabolite identification for KVH14 and metabolic stability testing for active 2,4-diaminoquinazolines will be performed using mouse and human liver microsomes to inform our synthesis efforts in Aim 1 to enhance oral bioavailability and systemic exposure. Several development-limiting toxicities (i.e. hepatotoxicity, cardiotoxicity, and CYP3A4 inhibition will be evaluated for active 2,4-diaminoquinazolines to prioritize compounds for further testing. Pharmacokinetics and tissue distribution of the most promising 2,4-diaminoquinazolines will be determined in mice to verify plasma and target organ exposure. PUBLIC HEALTH RELEVANCE: Visceral leishmaniasis and cutaneous leishmaniasis are parasitic diseases that affect millions of people per year in developing countries. The former disease is usually fatal without drug treatment, and the latter, which also impacts deployed U.S. military forces, causes disfiguring skin sores. Since the drugs that are currently given for visceral leishmaniasis and cutaneous leishmaniasis have several weaknesses, we are attempting to discover better drugs against these diseases based on new chemicals we have made that show promising antileishmanial properties.