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 真菌疾病每年影响约3亿人，并导致约160万人死亡。 尽管严重的真菌疾病的患病率很高，但没有传染病的药物开发领域 在过去的五十年中，取得的进步要比真菌学更少。在用于治疗的三类药物中 1950年代引入了浸润性真菌感染（IFIS），两性霉素B；硫唑是在 1970年代；而且echinocandins在2002年获得批准。不幸的是，这种进展缓慢不是因为 这些药物非常有效。确实，侵入性念珠菌病，侵入性曲霉病和 加密局局势是最常见的三个IFI，在30-40％，50％和 > 50％。此外，随着发病率，与IFIS相关的不良结果可能会恶化 抗真菌耐药性的耐药性继续升高。因此，该领域的明确共识是那个小说 抗真菌药物类型是传染病面临的最紧迫的非MET临床需求之一。 加快这一发展的一种方法是优化当前用于的药物的抗真菌活性 治疗其他疾病。与抗精神病药和抗过敏药有关的势噻嗪类分子类 我们和其他人已经显示出具有抗真菌特性。在初步研究中以优化这些 化合物，我们已经能够增加其抗真菌活性并降低其对 神经递质受体，剂量限制副作用的主要驱动力。在这里，我们提出了一个命中率 这些势噻嗪的发展集中在多巴胺/5-羟色胺受体的结构减少上 活性并降低多药外流亲和力。我们的目标是将3-4个分子推向初始动物功效 研究。为了实现这些目标，我们提出以下目的：1）基于药物化学的优化 苯噻嗪支架的抗真菌治疗指数； 2）表征抗抗的机制 新型氟苯胺和三氟吡嗪衍生物的候选活动； 3）体内药理学和功效 使用鼠感染模型对三个铅候选者进行测试。