氢化可的松与有机硝酸酯及呋咱氮氧化合物偶联物的合成、抗炎活性及安全性研究

以氢化可的松为先导物, 通过不同长度及柔度的连接基团, 分别与有机硝酸酯及呋咱氮氧化合物两类NO供体偶联, 合成了两个系列的衍生物I₁～I₇及II₁～II₈, 以期寻找到药效更强、安全性更高的新型抗炎药物. 衍生物的化学结构经MS, IR, ¹H NMR和元素分析确证. 初步抗炎活性筛选显示, 化合物I₃, II₃, II₅具有良好的抗炎活性; 进一步抗炎活性及安全性试验表明, II₅在急性、亚急性及免疫等多种炎症动物模型中活性与阳性对照物氢化可的松相当, 同时, II₅能够有效地防止骨丢失, 避免诱发高血压, 因而较之氢化可的松具有更好的安全性.

Synthesis, Anti-inflammatory Activity and Safety of Hydrocortisone Derivatives Coupled with Furoxans and Nitrates

In order to search for novel anti-inflammatory agents with high potency and safety, hydrocortisone was used as a leading compound and coupled with two groups of NO donors furoxans and nitrates through linkers with different length and flexibility. Compounds I₁～I₇ and II₁～II₈ were obtained and their structures were confirmed by MS, IR, ¹H NMR spectra and elemental analysis. Compounds I₃, II₃ and II₅ showed a good anti-inflammatory activity in the primary pharmacological screening. Furthermore II₅ also exhibited a potent anti-inflammatory activity in acute, sub-acute and immune inflammatory models. Compared with hydrocortisone II₅ could effectively prevent bone loss and avoid inducing hypertension in the safety screenings, indicating that it should have a better safety.