Carceller E, Merlos M, Giral M, Bartrolí J, García-Rafanell J, Forn J
Laboratory of Chemistry, Research Center, J. Uriach & Cía.S.A., Barcelona, Spain.
J Med Chem. 1992 Feb 21;35(4):676-83. doi: 10.1021/jm00082a007.
A series of 4-substituted 2-alkoxytetrahydrofuran derivatives featuring an acetal group were prepared and evaluated for PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Compound 2-[[N-acetyl-N-[[[2-(octadecyloxy)tetrahydrofuran-4- yl]methoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (4e, UR-11353) was selected for further development on the basis of its high activity and long-lasting action. The compound maintained a significant activity even 24 h after administration of a single dose of 1 mg/kg iv in the PAF-induced mortality test in mice and 10 h after administration of the same dose in the PAF-induced hypotension test in rats. Comparison with previously reported carba analogues suggests that the presence of the acetal group is the structural characteristic that confers its long-lasting activity.
制备了一系列具有缩醛基团的4-取代2-烷氧基四氢呋喃衍生物，并在PAF诱导的体外血小板聚集和体内低血压试验中评估了它们的PAF拮抗剂活性。基于其高活性和长效作用，选择了化合物2-[[N-乙酰基-N-[[[2-(十八烷氧基)四氢呋喃-4-基]甲氧基]羰基]氨基]甲基]-1-乙基吡啶氯化物（4e，UR-11353）进行进一步开发。在小鼠PAF诱导的死亡率试验中，单次静脉注射1mg/kg剂量后24小时，以及在大鼠PAF诱导的低血压试验中给予相同剂量后10小时，该化合物仍保持显著活性。与先前报道的碳环类似物的比较表明，缩醛基团的存在是赋予其长效活性的结构特征。
