Antileishmanial Lead Optimization of Quinazolines

描述（由申请人提供）：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）。我们的实验室已经发现，几种2，4-二氨基喹唑啉在低微摩尔至高纳摩尔浓度下具有体外抗利什曼原虫活性，并且该系列中的一种分子（KVH 14）在我们的VL小鼠模型中显示出有希望的疗效。在这个项目中，我们将进行重点铅优化研究，以确定喹唑啉化合物，可以作为临床前候选人治疗VL和/或CL。为此，我们提出以下目标：目标1：合成具有体内抗利什曼病活性的2，4-二氨基喹唑啉类化合物。基于领跑者化合物KVH 14，我们将继续进行结构-活性和结构-性质关系（SAR和SPR）研究，以增强抗利什曼原虫活性，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上的结构修饰以及喹唑啉的2-、4-、5-、6-、7-和8-位。目的2 2，4-二氨基喹唑啉类药物的抗利什曼原虫作用。将进行体外和体内测定以评估这些分子作为针对VL和CL的候选药物的潜力。评价这些分子对细胞内L. donovani（引起VL）、L. amazonensis（引起新世界CL的种）和L. major（其导致旧世界CL）将允许在VL（抗利什曼原虫IC 50 < 0.5 μ M且SI > 20）和CL（抗利什曼原虫IC 50 < 2 μ M且SI > 20）的鼠模型中鉴定待测试的分子。还将使用严重VL的仓鼠模型来辨别在我们的鼠VL模型中显示出突出的口服功效的喹唑啉是否应被认为是治疗该疾病表现的临床前候选物。目标3. 2，4-二氨基喹唑啉的ADME/Tox特征。将使用小鼠和人肝微粒体进行KVH 14的代谢物鉴别和活性2，4-二氨基喹唑啉的代谢稳定性试验，以告知我们在目标1中的合成工作，以提高口服生物利用度和全身暴露量。将评价活性2，4-二氨基喹唑啉的几种发育限制性毒性（即肝毒性、心脏毒性和CYP 3A 4抑制），以优先考虑化合物进行进一步检测。将在小鼠中测定最有前途的2，4-二氨基喹唑啉的药代动力学和组织分布，以验证血浆和靶器官暴露量。

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.