Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analog 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 cyclopent...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-01, Vol.30 (1), p.193-197
Main Authors: Collins, Paul W, Kramer, Steven W, Gasiecki, Alan F, Weier, Richard M, Jones, Peter H, Gullikson, Gary W, Bianchi, Robert G, Bauer, Raymond F
Format: Article
Language:English
Subjects:
Alicyclic compounds, terpenoids, prostaglandins, steroids
Alprostadil - analogs & derivatives
Alprostadil - pharmacology
Animals
Arbaprostil - analogs & derivatives
Arbaprostil - chemical synthesis
Arbaprostil - pharmacology
Arbaprostil - toxicity
Chemistry
Diarrhea - chemically induced
Dogs
Exact sciences and technology
Gastric Juice - drug effects
Gastric Juice - metabolism
Indicators and Reagents
Magnetic Resonance Spectroscopy
Male
Misoprostol
Organic chemistry
Preparations and properties
Prostaglandins
Prostaglandins E, Synthetic - chemical synthesis
Rats
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00384a032