SYNTHESIS AND EVALUATION OF NEW LOCAL ANTIINFLAMMATORY STEROIDS

新型局部抗炎类固醇的合成与评价

• 批准号: 6338798
• 负责人: HENRY J LEE
• 金额: $ 11.1万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338798
• 关键词: antiinflammatory agents; chemical structure function; corticosteroid analog; corticosteroid receptors; drug adverse effect; drug design /synthesis /production; drug interactions; drug metabolism; drug screening /evaluation; elastases; enzyme activity; esters; fatty acid biosynthesis; glycogen; high performance liquid chromatography; infrared spectrometry; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; paper chromatography; pituitary adrenal axis; prostaglandins; receptor binding; thin layer chromatography; transaminases

The use of corticosteroids in the treatment of inflammatory conditions has been limited primarily due to their systemic suppressive effects on the adrenal function and the immune system. To overcome this limitation, a focused effort has been made to synthesize locally active antiinflammatory steroids without systemic adverse effects based on the antedrug concept. In this approach, metabolically labile functional groups, alkyl carboxylates at various strategic positions of potent corticosteroids, have been introduced. The reduced systemic adverse effects of this steroidal antedrug are ascribed to rapid hydrolysis of the ester function into an inactive steroid acid upon entry into the circulation system. Thus the true antedrug acts only locally. It is proposed to synthesize a new group of steroidal antedrugs and evaluate them comprehensively with respect to their local and systemic pharmacological activity. To further delineate the mode of action of the new steroids, their receptor binding characteristics, effects on pituitary adrenal function, glycogen deposition, liberation of prostanoids and elastase will b studied. Results of these studies will yield valuable insight into the structural characteristics for the maximum separation of local anti-inflammatory activity from systemic adverse effects, and mode of action of these new steroids with the promise of providing a solid rational basis for development of new potent anti-inflammatory steroids devoid of systemic side effects.

皮质类固醇在炎性病症的治疗中的使用已经 主要是由于它们的全身抑制作用， 肾上腺功能和免疫系统。 为了克服这一限制， 已集中精力合成局部活性抗炎药 基于前药概念的无全身不良反应的类固醇。 在这种方法中，代谢不稳定的官能团，烷基， 羧酸酯在各种战略地位的有效皮质类固醇， 被介绍。 减少这种类固醇的全身不良反应 前药是由于酯官能团快速水解成 在进入循环系统时失去活性的类固醇酸。 因此 真正的前药只在局部起作用。 建议合成一个新的基团 的甾体类前药，并对其进行全面评价， 其局部和全身药理活性。 进一步界定 新类固醇的作用模式，它们的受体结合 特征，对垂体肾上腺功能的影响，糖原 研究前列腺素类和弹性蛋白酶的沉积、释放。 这些研究的结果将产生有价值的洞察结构 特点为最大限度分离局部消炎 活动的全身不良反应，以及这些新的作用方式 类固醇的承诺，提供了坚实的理性基础， 开发新的有效抗炎类固醇， 副作用.