Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues.
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.
Marivet
M C
MC
Département de Pharmacochimie Moléculaire, Centre de Neurochimie du CNRS, Strasbourg, France.
Bourguignon
J J
JJ
Lugnier
C
C
Mann
A
A
Stoclet
J C
JC
Wermuth
C G
CG
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D006152:Cyclic GMP / Q000378:metabolism; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D044005:Tetrahydroisoquinolines
D007093:Imidazoles; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D044005:Tetrahydroisoquinolines; C048819:4-(3,4-dibutoxybenzyl)-2-imidazolidinone; C035964:trequinsin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D020889:Rolipram