Nonsteroidal Cardiotonics. 2. The Inotropic Activity of Linear, Tricyclic 5-6-5 Fused Heterocycles

Article abstract of 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 β-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.