Studies on cardiotonic agents. VII. Potent cardiotonic agent KF15232 with myofibrillar Ca2+ sensitizing effect.
A series of novel 4,5-dihydro-5-methyl-6-(2 or 4-substituted 7-quinazolinyl)-3(2H)-pyridazinones was synthesized and examined for cardiotonic activity in anesthetized dogs. The 4-substituted aminoquinazolines generally showed potent and long-lasting inotropic activity. Fall in the activity was observed on the introduction of substituent at the 2-position of the quinazoline ring. The 3-substituted 4 (3H)-quinazolinimines generally exhibited weak activity. Ca2+ sensitizing effect of the 4-substituted amino derivatives was also examined in chemically skinned fiber from papillary muscle of guinea pig. The alkylamino derivatives exhibited small sensitizing effect, while the benzylamino derivatives exhibited large effect. Among them, KF15232 (Ix) was found to have the most potent cardiotonic and Ca2+ sensitizing activities.
Nomoto
Y
Y
Pharmaceutical Research Laboratories, Fuji, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Takai
H
H
Ohno
T
T
Kubo
K
K
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009210:Myofibrils / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D011799:Quinazolines; C070673:KF 15232; D002118:Calcium