Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogs

Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phosphodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivative...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1989-07, Vol.32 (7), p.1450-1457
Main Authors: Marivet, Michel C, Bourguignon, Jean Jacques, Lugnier, Claire, Mann, Andre, Stoclet, Jean Claude, Wermuth, Camille Georges
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3',5'-cyclic-nucleotide phosphodiesterase
Animals
blood vessels
Carbohydrates. Nucleosides and nucleotides
Cattle
Chemical Phenomena
Chemistry
Cyclic GMP - metabolism
Exact sciences and technology
Hydrolysis
Imidazoles - pharmacology
In Vitro Techniques
Isoquinolines - pharmacology
Molecular Conformation
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - enzymology
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Phosphodiesterase Inhibitors
Preparations and properties
Pyrrolidinones - pharmacology
Rolipram
smooth muscle
Tetrahydroisoquinolines
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Summary:Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phosphodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivatives differently substituted either at the pyrrolidinone or at the aromatic ring. Among these compounds, rolipram was the most active compound. Semirigid analogues were prepared and used for an evaluation of the active conformation of rolipram. Structural comparison with two other potent and chemically different smooth muscle cAMP-PDE inhibitors, trequinsin and Ro 20-1724, allows us to propose a first topological model of the smooth muscle cAMP-PDE pharmacophore.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00127a009