Chemistry and structure-activity relationships of C-17 unsaturated 18-cycloalkyl and cycloalkenyl analogues of enisoprost. Identification of a promising new antiulcer prostaglandin.
A series of delta 17 unsaturated cycloalkyl and cycloalkenyl analogues of enisoprost was synthesized to investigate the effects of omega chain unsaturation on gastric antisecretory activity and diarrheogenic side effects. Of these, the 17E, 18-cyclopentenyl analogue 5d displayed potent gastric antisecretory activity in dogs but very weak diarrheogenic properties in rats and is the most selective prostaglandin compound discovered in these laboratories. Structurally, 5d contains both a conjugated diene and tertiary allylic alcohol in the omega chain, and these chemical features impart some interesting oxidative and acid-catalyzed epimerization and allylic rearrangement reactivities, respectively.
Collins
P W
PW
Physical Methodology Department, G.D. Searle & Co., Skokie, Illinois 60077.
Gasiecki
A F
AF
Perkins
W E
WE
Gullikson
G W
GW
Bianchi
R G
RG
Kramer
S W
SW
Ng
J S
JS
Yonan
E E
EE
Swenton
L
L
Jones
P H
PH
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D015195:Drug Design; D005750:Gastric Juice / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D000527:Alprostadil; C054594:enisoprost