AMINOSTEROL COMPOUNDS AS THERAPEUTICS FOR ASTHMA

哮喘是一种复杂的气道炎症性疾病。目前的治疗采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一部分患者的副作用有关。因此，需要开发有效抑制哮喘反应且缺乏皮质类固醇的药理学性质的新型药物来治疗这种疾病。我们已经确定了一类新的低分子量分子，在体外阻断淋巴细胞异型聚集有强大的效果。体内数据表明，这些化合物在抑制啮齿动物哮喘模型中对抗原的哮喘样应答方面具有有效活性。使用组合的方法和结构活性关系在体外，我们已经开发了新的类似物的原型，在抑制淋巴细胞聚集在体外具有更强的活性。该资助的目的是：1）制备氨基甾醇原型及其类似物的分析纯制剂，用于体内毒性研究; 2）使用这些化合物进行体内研究，以确定其抑制对抗原的哮喘样反应的功效。拟议的商业应用：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的使用具有作为新型抗炎和哮喘药物商业化的广泛潜力。我们的目的是追求这些氨基甾醇化合物作为气雾剂或口服药物治疗哮喘的产生和发展。Magainin在开发这类化合物方面处于独特的地位，因为我们的知识产权地位受到多项专利的保护，这些专利涵盖了物质的组成及其在广泛适应症中的用途。

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.