(Imidazolylphenyl)pyrrol-2-one inhibitors of cardiac cAMP phosphodiesterase.
Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as potential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brain cAMP PDE isozyme, as a lead structure and was guided by a model which describes the features required for potent inhibition of the cardiac isozyme. Syntheses for the new compounds are described, together with the results of theoretical and crystallographic studies aimed toward ascertaining their three-dimensional structures. The activities of these compounds as inhibitors of the cardiac and brain cAMP PDE isozymes and their positive inotropic activity in ferret papillary muscle are also reported. Selected compounds were further examined in an in vivo hemodynamic model. One compound 1,5-dihydro-4-[4-(1H-imidazol-1- yl)phenyl]-3-methyl-2H-pyrrol-2-one, was identified as a potent and selective positive inotropic agent and inhibitor of cardiac cAMP PDE.
Lampe
J W
JW
Berlex Laboratories, Cedar Knolls, New Jersey 07927.
Chou
Y L
YL
Hanna
R G
RG
Di Meo
S V
SV
Erhardt
P W
PW
Hagedorn
A A
AA
Ingebretsen
W R
WR
Cantor
E
E
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D011760:Pyrrolidinones; C080862:1,5-dihydro-4-(4-(1H-imidazol-1-yl)phenyl)-3-methyl-2H-pyrrol-2-one; D015105:3',5'-Cyclic-AMP Phosphodiesterases