Nonsteroidal cardiotonics. 2. The inotropic activity of linear, tricyclic 5-6-5 fused heterocycles

• Published in: Journal of medicinal chemistry 1989-07, Vol.32 (7), p.1481-1491
• Main Authors: Von der Saal, Wolfgang, Hoelck, Jens Peter, Kampe, Wolfgang, Mertens, Alfred, Mueller-Beckmann, Bernd
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cardiotonic Agents - chemical synthesis; Cats; Cyclic AMP - biosynthesis; Dogs; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - pharmacology; Rats; Structure-Activity Relationship; Vasoconstrictor Agents - chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00127a015

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.