SYNTHESIS & EVALUATION OF NEW ANTIINFLAMMATORY STEROIDS

皮质类固醇在治疗炎症性疾病中的应用受到限制，主要是由于其对肾上腺功能和免疫系统的系统性抑制作用。为了克服这一局限性，基于前药概念，已经集中精力合成局部活性抗炎类固醇而没有全身不良反应。在这种方法中，前药被设计为在应用部位发挥作用，但要经历体循环。因此，真正的前药作用于局部，没有全身不良反应。建议合成一组新的甾体类前药，并对其局部至全身药理活性进行全面评价。为了进一步描述新类固醇的作用模式，将研究其受体结合特征、对垂体肾上腺功能、糖原沉积、前列腺素类和一氧化氮（NO）释放的影响。这些研究的结果将产生有价值的深入了解的结构特征，最大限度地分离局部抗炎活性从全身不良反应，和这些非全身性抗炎类固醇的作用模式，提供了一个坚实的合理的基础，为开发新的有效的抗炎类固醇没有全身副作用的承诺。

The use of corticosteroids in the treatment of inflammatory conditions has been limited primarily due to their systematic suppressive effects on the adrenal function and the immune system. To overcome this limitation, a focused effort has been made to synthesize locally active anti- inflammatory steroids without systemic adverse effects based on the antedrug concept. In this approach, antedrugs are designed to exert their actions at the application site, but to undergo the systemic circulation. Thus, the true antedrug acts locally and is devoid of systemic adverse effects. It is proposed to synthesize a new group of steroidal antedrugs and evaluate them comprehensively with respect to their local to systemic pharmacological activities. 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 nitric oxide (NO) will be 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 the mode of action of these non-systemic anti-inflammatory steroids with the promise of providing a solid rational basis for development of new potent anti-inflammatory steroids devoid of systemic side effects.