一氧化氮供体型塞曲司特衍生物的设计、合成和抗哮喘活性

Design, synthesis and antiasthmatic activities of NO-donatingseratrodast derivatives

目的 寻找新型抗哮喘药物。方法 以抗哮喘药塞曲司特(SD)为母核,将不同类型的一氧化氮(NO)供体,包括嗯三唑类、N-羟基胍类和呋咱氮氧化合物类与其相偶联;通过对乙酰胆碱-组胺所致豚鼠哮喘的抑制作用来评价偶联物的抗哮喘活性;研究偶联物的NO释放作用。结果 合成了9个未见文献报道的目标化合物I1-9,结构经IR,NMR,MS及元素分析确证。初步药理试验表明,目标化合物I2-7和I9具有显著的抗哮喘活性(引喘潜伏期由sD的10 s延长到26～62 s),其中I4,I6,I7的活性强于SD(P<0.05,P<0.01),体外释放NO的Cmax分别为0.187 8,0.139 3和0.247 3 mg·L-1。结论 NO供体型塞曲司特衍生物具有进一步研究的价值。

Aim To search for novel antiasthmatic agents. Methods Coupling seratrodast (SD) , an antiasthmatic drug, with several different types of NO donors including oxatriazoles, 7V-hydroxyguanidines and furoxans; evaluating the antiasthmatic effects of coupled compounds by determining their inhibitory activity of guinea pig asthma induced by acetylcholine and histamine; and assessing NO releasing ability. Results Nine novel target compounds ( I1-9 ) were synthesized, and their structures were established by IR, NMR, MS and elemental analysis. Preliminary pharmacological test showed that most of the compounds showed high antiasthmatic activities ( the latent period of induced asthma was prolonged from 10 s (SD) to 26 -62 s) , among which 3 compounds (I4, I6, I7) were more potent than SD (P <0. 05 ,P <0. 01) and released more NO than others. The maximum concentrations ( Cmax) of NO-release in vitro were 0. 187 8, 0. 139 3 and 0. 247 3 mg·L-1, respectively. Conclusion NO donating-SD derivatives are worthy to be futher investigated.