Cardiotonic agents. 2. Synthesis and structure-activity relationships of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones: a new class of positive inotropic agents.
A series of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds were synthesized and evaluated for positive inotropic activity. Most members of this series produced dose-related increases in myocardial contractility that were associated with relatively minor increases in heart rate and decreases in systemic arterial blood pressure. Introduction of a methyl substituent at the 5-position of 1 (CI-914) produced the most potent compound in this series (11, CI-930). Compound 1 is more potent than amrinone whereas compound 11 is more potent than milrinone. The inotropic effects of 1 and 11 are not mediated via stimulation of beta-adrenergic receptors. Selective inhibition of cardiac phosphodiesterase fraction III represents the principal component of the positive inotropic action of 1 and 11.
Sircar
I
I
Duell
B L
BL
Bobowski
G
G
Bristol
J A
JA
Evans
D B
DB
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D011724:Pyridazines