Nonsteroidal cardiotonics. 2. The inotropic activity of linear, tricyclic 5-6-5 fused heterocycles.
We previously reported the structure-activity relationships (SAR) of adibendan (1), a potent and long-acting cardiotonic. This paper describes the synthesis of a novel series of linear, tricyclic fused heterocycles of the 5-6-5 type. The compounds were evaluated for positive inotropic activity in anesthetized rats, cats, and dogs. Changes in left ventricular dP/dt were measured as an index of cardiac contractility. The increase in contractility was not mediated via stimulation of beta-adrenergic receptors. The data revealed the intrinsic positive inotropic activity of the parent compound of this series, 5,7-dihydro-7,7-dimethylpyrrolo[2,3-f]benzimidazol-6(1H)-one (2). The structural features that impart optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers to measure ventricular pressures, and their effect on left ventricular dP/dt was compared with that of 1, pimobendan, and indolidan. After administration of 1 mg/kg, 1, 3, 7, 19, 22, 24, 31, 54, pimobendan, and indolidan were equipotent, but only with 1, 31, pimobendan, and indolidan, durations of action exceeded 6 h.
von der Saal
W
W
Department of Chemistry, Boehringer Mannheim GmbH, Mannheim, West Germany.
Hölck
J P
JP
Kampe
W
W
Mertens
A
A
Müller-Beckmann
B
B
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000138:chemical synthesis; D002415:Cats; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis
D002316:Cardiotonic Agents; D006571:Heterocyclic Compounds; D014662:Vasoconstrictor Agents; D000242:Cyclic AMP; D002118:Calcium