AMINOSTEROL COMPOUNDS AS THERAPEUTICS FOR ASTHMA

哮喘是一种复杂的呼吸道炎症性疾病。目前的治疗方法是使用吸入性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，但对严重形式的疾病效果较差。此外，长期使用皮质类固醇与部分患者的副作用有关。因此，开发有效抑制哮喘反应且缺乏皮质类固醇药理学特性的新型药物是治疗这种疾病的理想方法。我们已经确定了一类新的低分子分子，它们在体外具有有效的阻断淋巴细胞异型聚集的作用。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很强的活性。利用组合方法和体外构效关系，我们开发了新的原型类似物，在体外具有更强的抑制淋巴细胞聚集的活性。这笔赠款的目的是：1)为体内毒性研究准备分析纯的氨基甾醇原型及其类似物；以及2)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有效性。建议的商业应用：使用新型低分子化合物，能够通过非皮质类固醇机制抑制抗原的哮喘反应，作为抗炎和哮喘新药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发展，作为治疗哮喘的气雾剂或口服药物。由于我们的知识产权地位，Mainin在开发这类化合物方面处于独特的地位，我们的知识产权地位受到多项专利的保护，这些专利涵盖物质的组成及其在各种适应症中的用途。

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.