Synthesis and pharmacological characterization of functionalized 2-pyridones structurally related to the cardiotonic agent milrinone.
A new class of cardiotonic agents characterized by a 2-pyridone structure was synthesized. Appropriate sym-2-dimethylaminomethylene-1,3-diones reacted with methylcyanoacetate to afford the desired compounds. These derivatives were evaluated for their ability in inducing cardiotonic response on guinea pig isolated myocardial preparations. Compound 8b increased atrial contractility to an extent which is significantly higher than that of milrinone, the parent drug used as a reference compound. The pharmacological characterization and the docking studies performed on 8b highlighted its selective mechanism of action via type 3 PDE (PDE3) inhibition.
Fossa
Paola
P
Department of Pharmaceutical Sciences, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
Menozzi
Giulia
G
Dorigo
Paola
P
Floreani
Maura
M
Mosti
Luisa
L
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D020105:Milrinone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011728:Pyridones / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D015363:Quinolones; C021294:cilostamide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone