Antileishmanial Lead Optimization of Quinazolines

喹唑啉类抗利什曼原药先导化合物的优化

• 批准号: 8359401
• 负责人: KARL A WERBOVETZ
• 金额: $ 24.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359401
• 关键词: Affect; Africa; Americas; Biological Assay; Biological Availability; CYP3A4 gene; Cardiotoxicity; Characteristics; Chemicals; Clinical; Cutaneous Leishmaniasis; Developing Countries; Development; Digit structure; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Evaluation; Exhibits; Goals; Hamsters; Hepatotoxicity; Human; In Vitro; India; Infection; Inhibitory Concentration 50; Investigation; Lead; Leishmania; Leishmania donovani; Leishmaniasis; Life; Liver; Liver Microsomes; Measures; Metabolic; Military Personnel; Modeling; Modification; Mus; Oral; Organ; Parasitemia; Parasitic Diseases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Positioning Attribute; Property; Quinazolines; Research; Route; Series; Skin; Skin Ulcer; Solubility; Structure; Symptoms; Testing; Toxic effect; United States; Visceral; Visceral Leishmaniasis; analog; base; diaminoquinazoline; drug candidate; improved; in vivo; indexing; interest; intraperitoneal; macrophage; neglect; pre-clinical; scaffold; social stigma; stability testing

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.

描述（由适用提供）：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，在低微摩尔到高纳摩尔浓度下，几种2,4-二氨基喹唑啉具有体外抗抗精性活性，并且该系列中的一个分子（KVH14）在我们的VL鼠模型中显示出有希望的效率。在这个项目中，我们将进行集中的铅优化研究，以识别可以用作治疗VL和/或CL的临床前候选物质的喹唑啉化合物。为此，我们提出了以下目的：目标1：与体内抗精神经会活动的2,4-二氨基喹唑啉合成。基于Frontrunner Compound KVH14，我们将继续进行结构活性和结构 - 特性关系（SAR和SPR）研究，以增强抗精性活动，同时维持或改善物理性质。优化工作将主要集中于喹唑啉支架以及喹唑啉2、4，-5-，6-，7-和8位的结构修饰。 AIM 2对2,4-二氨基喹唑啉的抗精神经会评估。将在体外和体内测定评估这些分子的潜力，因为将对针对VL和CL的药物进行候选。评估这些分子对细胞内多诺瓦尼（引起VL），亚马逊河（L. amazonensis）（引起新世界CL的物种）和Major（导致旧世界CL）的效力的评估，允许在鼠模型中识别分子的识别（抗菌IC50 <0.50 <0.5 <0.5级和Si> 20）和SI> 20 iC> 20 i> cl（MI> 20）。 Si> 20）。严重VL的仓鼠模型也将用于辨别喹唑啉在我们的鼠VL模型中表现出杰出的口腔效率是否应被视为治疗这种疾病表现的临床前候选者。目标3。2,4-二氨基喹唑啉的ADME/TOX分析。将使用小鼠和人肝微粒体进行活性2,4-二氨基喹唑啉的KVH14和代谢稳定性测试的代谢物鉴定，以告知我们在AIM 1中的合成工作，以增强口服生物利用度和全身暴露。将评估几种开发限制毒性（即肝毒性，心脏毒性和CYP3A4抑制作用，将评估活跃的2,4-二氨基喹唑啉，以优先进行进一步测试的化合物。将确定最有希望的2,4-二氨基Quinazoline的药代动力学和组织分布的药代动力学和组织分布。 公共卫生相关性：内脏利什曼病和皮肤利什曼病是寄生疾病，每年影响数百万的发展中国家。前者通常没有药物治疗通常是致命的，而后者也影响部署的美国军事力量，会导致皮肤疮毁容。由于目前针对内脏利什曼病和皮肤利什曼病的药物有几个弱点，因此我们试图根据我们制作的新化学物质来发现对这些疾病的更好的药物，我们使该疾病显示出有望的抗精神经会特性。