Collins P W, Gasiecki A F, Perkins W E, Gullikson G W, Jones P H, Bauer R F
Gastrointestinal Diseases Research Department, G.D. Searle & Co., Skokie, Illinois 60077.
J Med Chem. 1989 May;32(5):1001-6. doi: 10.1021/jm00125a013.
By use of standard cuprate methodology, a series of 18-cycloalkyl analogues of enisoprost was prepared in an effort to impede omega chain metabolism and prolong duration of gastric antisecretory activity. An initial product of omega chain oxidation, the C-20 hydroxy analogue, was also synthesized for pharmacological comparison. The cyclopropyl, cyclobutyl, and cyclopentyl analogues were approximately one-fourth as potent as enisoprost in inhibiting gastric acid secretion, while the cyclohexyl and cycloheptyl analogues showed very weak activity, and the 20-hydroxy compound was inactive at a dose 100 times the ED50 of enisoprost. The cyclobutyl compound had a longer duration of antisecretory action than enisoprost and the other cycloalkyl analogues. The cycloalkyl analogues unexpectedly possessed low diarrheogenic activity in rats.
通过使用标准的铜酸盐方法，制备了一系列依尼前列素的18-环烷基类似物，以试图阻碍ω链代谢并延长胃抗分泌活性的持续时间。还合成了ω链氧化的初始产物C-20羟基类似物用于药理学比较。环丙基、环丁基和环戊基类似物在抑制胃酸分泌方面的效力约为依尼前列素的四分之一，而环己基和环庚基类似物显示出非常弱的活性，并且20-羟基化合物在剂量为依尼前列素ED50的100倍时无活性。环丁基化合物的抗分泌作用持续时间比依尼前列素和其他环烷基类似物更长。环烷基类似物在大鼠中意外地具有低致腹泻活性。
