Hit-to-lead optimization of broad spectrum antifungal phenothiazines

广谱抗真菌吩噻嗪类化合物的命中至先导化合物优化

基本信息

批准号：
10416079
负责人：
Damian J Krysan
金额：
$ 19.09万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-02 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416079
关键词：
Adopted Affect Affinity Amphotericin B Anti-Infective Agents Antiemetics Antifungal Agents Antifungal Therapy Antipsychotic Agents Area Aspergillosis Aspergillus Azole resistance Azoles Biological Assay Biological Availability Candida Candida albicans Candida auris Candidiasis Central Nervous System Infections Cessation of life Clinical Coccidioides Communicable Diseases Consensus Cryptococcal Meningitis Cryptococcus Cryptococcus neoformans Data Development Disease Disseminated candidiasis Dopamine Dopamine Receptor Dose Dose-Limiting Drug Efflux Drug usage Fluphenazine Fungal Drug Resistance Fusarium Goals Grant High Prevalence Histoplasma Human Incidence Industrial fungicide Infection Lead Life Modeling Morbidity - disease rate Mucor Multi-Drug Resistance Mus Mycoses National Institute of Mental Health Neurotransmitter Receptor Oral Organ Outcome Parents Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacopoeias Phase II Clinical Trials Phenothiazines Polyenes Property Psychotropic Drugs Publishing Pump Resistance Structure Testing The science of Mycology Therapeutic Index Trifluoperazine animal efficacy base drug candidate drug development echinocandin resistance efficacy study efficacy testing efflux pump experimental study fungus human model improved in vivo lead candidate lead optimization mortality mouse model neurotransmitter antagonist novel novel therapeutics pathogenic fungus pharmacokinetics and pharmacodynamics preclinical development resistant strain scaffold screening program serotonin receptor side effect

项目摘要

PROJECT SUMMARY Fungal diseases affect an estimated 300 million people a year and lead to approximately 1.6 million deaths. Despite the high prevalence of serious fungal diseases, no area of infectious disease drug development has made less progress in the last fifty years than mycology. Of the three primary classes of drugs used to treat invasive fungal infections (IFIs), amphotericin B was introduced in the 1950s; azoles were developed in the 1970s; and the echinocandins were approved in 2002. Unfortunately, this slow rate of progress is not because these drugs are highly effective. Indeed, the mortality rates for invasive candidiasis, invasive aspergillosis, and cryptococcal meningitis, three of the most common IFIs, remain unacceptably high at 30-40%, 50%, and >50%, respectively. Furthermore, the poor outcomes associated with IFIs are likely to worsen as the incidence of antifungal drug resistance continues to rise. Accordingly, the clear consensus in the field is that novel classes of antifungal drugs represent one of the most pressing un-met clinical needs facing infectious disease. One approach to expediting this development is to optimize the antifungal activity of drugs currently used to treat other diseases. The phenothiazine class of molecules related to antipsychotic and antiemetic medications has been shown by us and others to have antifungal properties. In preliminary studies toward optimizing these compounds, we have been able to increase their antifungal activity and decrease their affinity for neurotransmitter receptors, the prime driver of dose limiting side effects. Here, we propose a hit-to-lead development of these phenothiazines focusing on structure guided reduction in dopamine/serotonin receptor activity and reducing multi drug efflux affinity. Our goal is to advance 3-4 molecules into initial animal efficacy studies. To achieve these goals we propose the following aims: 1) medicinal chemistry-based optimization of the antifungal therapeutic index of the phenothiazine scaffold; 2) characterize the mechanism of increased anti- candidal activity of novel fluphenazine and trifluoperazine derivatives; and 3) in vivo pharmacology and efficacy testing of three lead candidates using murine infection models.

项目概要据估计，真菌病每年影响 3 亿人，并导致约 160 万人死亡。尽管严重真菌病的患病率很高，但传染病药物开发领域尚未取得进展。过去五十年中取得的进展不如真菌学。用于治疗的三类主要药物中侵袭性真菌感染 (IFIs)，两性霉素 B 于 20 世纪 50 年代推出；唑类是在 20 世纪 70 年代；棘白菌素于 2002 年获得批准。不幸的是，进展缓慢并不是因为这些药物非常有效。事实上，侵袭性念珠菌病、侵袭性曲霉病和隐球菌性脑膜炎是三种最常见的 IFI，其发病率仍然高得令人难以接受，分别为 30-40%、50% 和分别>50%。此外，随着 IFI 发生率的增加，与 IFI 相关的不良结果可能会进一步恶化。抗真菌药物耐药性持续上升。因此，该领域的明确共识是新颖的各类抗真菌药物代表了传染病面临的最紧迫的未满足的临床需求之一。加速这一发展的一种方法是优化目前用于治疗的药物的抗真菌活性。治疗其他疾病。与抗精神病药和止吐药相关的吩噻嗪类分子我们和其他人已证明具有抗真菌特性。在优化这些的初步研究中化合物，我们已经能够增加它们的抗真菌活性并降低它们的亲和力神经递质受体，剂量限制性副作用的主要驱动因素。在这里，我们建议采用“点击领先”的方式这些吩噻嗪类药物的开发重点是结构引导的多巴胺/血清素受体还原活性并降低多药物流出亲和力。我们的目标是使 3-4 个分子达到初始动物功效研究。为了实现这些目标，我们提出以下目标：1）基于药物化学的优化吩噻嗪支架的抗真菌治疗指数； 2) 表征增强抗性的机制新型氟奋乃静和三氟拉嗪衍生物的念珠菌活性； 3）体内药理学和功效使用小鼠感染模型测试三个主要候选者。