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

• 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
• 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

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.

项目摘要 据估计，真菌疾病每年影响3亿人，并导致约160万人死亡。 尽管严重的真菌疾病的发病率很高，但没有一个传染病药物开发领域 在过去的50年里，真菌学的进展不如真菌学。在用于治疗糖尿病的三种主要药物中 侵袭性真菌感染（IFIs），阿替霉素B在20世纪50年代被引入; 20世纪70年代;棘白菌素于2002年获得批准。不幸的是，这种缓慢的进展速度不是因为 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，三种最常见的IFIs，仍然高得令人无法接受，分别为30- 40%，50%， > 50%。此外，与国际金融机构相关的不良结果可能会随着发病率的增加而恶化。 抗真菌药物的耐药性继续上升。因此，该领域的明确共识是， 抗真菌药物的种类代表了感染性疾病面临的最迫切的未满足的临床需求之一。 加快这种发展的一种方法是优化目前用于治疗真菌感染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 已经被我们和其他人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，降低它们的亲和力， 神经递质受体，剂量限制副作用的主要驱动力。在这里，我们提出了一个打击领导 这些吩噻嗪类药物的开发重点是多巴胺/5-羟色胺受体的结构导向性降低 活性和降低多药物外排亲和力。我们的目标是推进3-4个分子进入初始动物疗效 问题研究为了实现这些目标，我们提出了以下目标：1）基于药物化学的优化， 吩噻嗪支架的抗真菌治疗指数; 2）表征抗真菌治疗指数增加的机制。 新型氟奋乃静和三氟拉嗪衍生物的念珠菌活性;和3）体内药理学和功效 使用鼠感染模型测试三种主要候选物。