Potentiators of fluconazole activity in Candida

氟康唑对念珠菌活性的增效剂

• 批准号: 6855396
• 负责人: Penelope N. Markham
• 金额: $ 4.52万
• 依托单位: PROTEZ PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855396
• 关键词: Candida albicans; antifungal agents; candidiasis; combination chemotherapy; disease /disorder model; drug design /synthesis /production; drug interactions; drug screening /evaluation; fluconazole; laboratory mouse; multidrug resistance

DESCRIPTION (provided by applicant): The goal of this Phase II SBIR project is to develop a clinically useful potentiator of the most widely used antifungal drugs, azoles. The major shortcoming of azole drugs is that they do not kill fungi but merely inhibit their growth. In fact, for the most medically important fungal pathogen, Candida albicans, this growth inhibition is only partial. The survival of the pathogen in the presence of the drug is the likely cause of the recurrence of fungal infections and emergence of azole resistance. Our Phase I studies identified two compounds in whose presence azoles become strongly fungicidal. These compounds show no antifungal activity on their own and no toxicity to human cells in culture. Structural derivatives of these two leads, displaying improved activity and pharmacological properties, will be obtained through intensive synthetic efforts. The biological activity of these derivatives will be thoroughly characterized in vitro. Their ability to improve antifungal activity of fluconazole will be tested in a murine model of systemic candidiasis. Finally, the molecular mechanism of action of the potentiators will be investigated in biochemical and genetic experiments. It is expected that the compounds developed in this project will significantly improve the improve the effectiveness of antifungal therapy. PROPOSED COMMERCIAL APPLICATION: The commercial product envisioned is a fungicidal combination of fluconazole with an adjuvant that potentiates antifungal activity. Such a product would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections

描述（由申请人提供）：第二阶段 SBIR 项目的目标是 开发临床上最广泛使用的抗真菌药物的增效剂 药物，唑类。唑类药物的主要缺点是不能杀死 真菌，但仅仅抑制其生长。事实上，对于大多数医学 重要的真菌病原体，白色念珠菌，这种生长抑制作用仅 部分的。病原体在药物存在的情况下很可能存活 真菌感染复发和唑类耐药性出现的原因。 我们的第一阶段研究确定了两种化合物，其中唑类会变成 具有很强的杀菌作用。这些化合物本身没有抗真菌活性 对培养的人体细胞没有毒性。这两个的结构衍生物 显示出改善的活性和药理学特性的先导化合物将被 经过大量的合成努力而获得。这些物质的生物活性 衍生物将在体外得到彻底的表征。他们的能力有待提高 氟康唑的抗真菌活性将在小鼠全身模型中进行测试 念珠菌病。最后，增效剂的分子作用机制 将在生化和遗传实验中进行研究。预计 该项目开发的化合物将显着改善 提高抗真菌治疗的有效性。 拟议的商业应用： 设想的商业产品是氟康唑与增强抗真菌活性的佐剂的杀真菌组合。这样的产品将对全身念珠菌感染的治疗和预防治疗选择产生重大影响