Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analogue of misoprostol.
A stereospecific synthesis and the gastric antisecretory and diarrheal activity of a 3E,5Z diene analogue of misoprostol are described. The key intermediate in the synthesis was an alpha chain truncated acetylene that was obtained by a cuprate/enolate capture procedure on the corresponding cyclopentenone. Palladium-catalyzed coupling of the acetylene with methyl 4-iodo-3(E)-butenoate provided the conjugated enyne. Although selective hydrogenation of the enyne with Lindlar catalyst failed, the desired 3E,5Z diene was obtained with P-2 nickel as catalyst. The diene was about 3 times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001101:Arbaprostil / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D005750:Gastric Juice / Q000187:drug effects / Q000378:metabolism*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D016595:Misoprostol; D011459:Prostaglandins E, Synthetic / Q000138:chemical synthesis*; D051381:Rats; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011459:Prostaglandins E, Synthetic; D016595:Misoprostol; C050945:15-deoxy-16-methyl-16-hydroxy-3,4-didehydroprostaglandin E2 methyl ester; D000527:Alprostadil; D001101:Arbaprostil