Cardiotonic agents. 7. Inhibition of separated forms of cyclic nucleotide phosphodiesterase from guinea pig cardiac muscle by 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds. Structure-activity relationships and correlation with in vivo positive inotropic activity.
The structure-activity relationships of a series of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds were investigated for the in vivo inhibition of different forms of cyclic nucleotide phosphodiesterase (PDE) isolated from guinea pig ventricular muscle. With few exceptions, these 4,5-dihydropyridazinones were potent inhibitors of cardiac type III phosphodiesterase, which is a low Km, cyclic AMP specific form of the enzyme. The inhibitory effects on cardiac type I and type II phosphodiesterase, both of which hydrolyze cyclic AMP as well as cyclic GMP, were minimal. The most selective PDE III inhibitor was CI-930 (10), the 5-methyl analogue of imazodan (CI-914, 1), with an IC50 of 0.6 microM. The most potent inhibitor of PDE III was the 4,5,6,7-tetrahydrobenzimidazole analogue of 10 (31), with an IC50 of 0.15 microM. This paper describes the structural features that impart both selectivity for inhibiting type III phosphodiesterase and potency of inhibition. In addition, correlations between in vitro PDE inhibitory potency, in vivo positive inotropic potency, and physicochemical properties are discussed.
Sircar
I
I
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Weishaar
R E
RE
Kobylarz
D
D
Moos
W H
WH
Bristol
J A
JA
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D007093:Imidazoles; D011724:Pyridazines; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases