AMINOSTEROL COMPOUNDS AS THERAPEUTICS FOR ASTHMA

氨基甾醇化合物作为哮喘的治疗剂

• 批准号: 6075001
• 负责人: ROY C. LEVITT
• 金额: $ 10万
• 依托单位: GENAERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2001-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6075001
• 关键词: asthma; bronchodilators; cholestane compound; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; lymphocyte; respiratory disorder chemotherapy

Asthma is a complex inflammatory disease of the airway. Current treatments employ the use of inhaled bronchodilators and corticosteroids. While these medicines are effective for most cases of asthma, they are less effective in severe forms of the disease. Moreover, the chronic use of corticosteroids has been associated with side effects in a subset of patients. Therefore the development of novel medications that are effective in suppressing the asthmatic response and lack the pharmacological properties of corticosteroids is desirable for the treatment of this disorder. We have identified a novel class of low molecular weight molecules that have potent effects on blocking lymphocyte heterotypic aggregations in vitro. in vivo data suggest that these compounds have potent activity in suppressing asthmatic-like responses to antigen in rodent models of asthma. Using combinatorial approaches and structure activity relationships in vitro, we have developed new analogs of the prototype that have more potent activity in suppressing lymphocyte aggregation in vitro. The aims of this grant are: 1) prepare analytically pure preparations of the aminosterol prototype and its analogs for in vivo toxicity studies; and 2) perform in vivo studies with these compounds to determine their efficacy in suppressing asthmatic-like responses to antigen. PROPOSED COMMERCIAL APPLICATIONS: The use of novel low molecular weight compounds that are able to suppress the asthmatic response to antigen via non-corticosteroidal mechanisms have a broad potential for commercialization as new anti- inflammatory and asthma medicines. It is our intent to pursue the generation and development of these aminosterol compounds as an aerosol or oral medication for the treatment of asthma. Magainin is in a unique position to develop compounds of this class because of our intellectual property position, which is secured by multiple patents that cover composition of matter and their use in a broad range of indications.

哮喘是一种复杂的气道炎症性疾病。目前的治疗采用吸入支气管扩张剂和皮质类固醇。虽然这些药物对大多数哮喘病例有效，但对严重的哮喘病例效果较差。此外，长期使用皮质类固醇与部分患者的副作用有关。因此，需要开发能够有效抑制哮喘反应并且缺乏皮质类固醇药理学特性的新药物来治疗这种疾病。我们已经鉴定出一类新型低分子量分子，它们对体外阻断淋巴细胞异型聚集具有有效作用。体内数据表明，这些化合物在抑制哮喘啮齿动物模型中对抗原的哮喘样反应方面具有有效的活性。利用体外组合方法和结构活性关系，我们开发了原型的新类似物，其在体外抑制淋巴细胞聚集方面具有更有效的活性。该资助的目的是：1）制备用于体内毒性研究的氨基甾醇原型及其类似物的分析纯制剂； 2) 使用这些化合物进行体内研究，以确定它们在抑制对抗原的哮喘样反应方面的功效。拟议的商业应用：使用能够通过非皮质类固醇机制抑制对抗原的哮喘反应的新型低分子量化合物作为新型抗炎和哮喘药物具有广泛的商业化潜力。我们的目的是追求这些氨基甾醇化合物的产生和开发，作为治疗哮喘的气雾剂或口服药物。 Magainin 在开发此类化合物方面处于独特的地位，因为我们的知识产权地位得到了多项专利的保障，这些专利涵盖了物质的成分及其在广泛的适应症中的用途。