18-cycloalkyl analogues of enisoprost.
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.
Collins
P W
PW
Gastrointestinal Diseases Research Department, G.D. Searle & Co., Skokie, Illinois 60077.
Gasiecki
A F
AF
Perkins
W E
WE
Gullikson
G W
GW
Jones
P H
PH
Bauer
R F
RF
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D000527:Alprostadil; C054594:enisoprost