Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure.
A novel series of analogues of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl) phenyl]ethenyl]-3(2H)-pyridazinone was synthesized as a variation on the imazodan series. The compounds were evaluated for (i) hemodynamic activity, (ii) cyclic AMP-phosphodiesterase inhibitory activity (human platelets and guinea pig heart tissue), and (iii) platelet aggregation inhibitory activity. The insertion of the ethenyl moiety between the phenyl and dihydropyridazinone rings produced novel compounds that retained the potent inotropic/vasodilator activity of the parent imazodan series and enhanced the platelet aggregation inhibitory potency. Compound 3d, the most potent in this series, demonstrated in vivo antithrombotic activity. The synthesis and the biological activity of these new pyridazinone analogues are reported.
Sircar
I
I
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Harbor, Michigan 48105.
Steffen
R P
RP
Bobowski
G
G
Burke
S E
SE
Newton
R S
RS
Weishaar
R E
RE
Bristol
J A
JA
Evans
D B
DB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
D002316:Cardiotonic Agents; D005343:Fibrinolytic Agents; D007093:Imidazoles; D011724:Pyridazines; D014665:Vasodilator Agents; D015105:3',5'-Cyclic-AMP Phosphodiesterases