Inotropic agents. Synthesis and structure-activity relationships of new milrinone related cAMP PDE III inhibitors.
The synthesis of 6-substituted 5-acyl-1,2-dihydro-2-oxo-3-pyridinecarbonitriles 1b,c, 1,2,5,6,7,8-hexahydro-2,5-dioxo-3-quinolinecarbonitriles 1d-g and esters of 5-cyano-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylic acid 2b-e is described. In the case of 1e and 1f, a careful elucidation of the reaction mechanism is discussed. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea pigs. The methyl and the benzyl esters 2b and 2e showed an appreciable positive inotropic activity when compared to milrinone. A fitting study with the DISCO (Distance Comparison) model has been carried out on 2e. This modeling approach allowed for the improvement of the pharmacophoric requirements for a better interaction with the cAMP-specific PDE (PDE III), thought to be the final biological target of these cardiotonic agents.
Fossa
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Dipartimento di Scienze Farmaceutiche, Università di Genova.
Boggia
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Lo Presti
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Mosti
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Dorigo
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Floreani
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D012110:Reserpine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone