We discovered that 6 (N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide) is a potent positive inotrope in dogs, and we have prepared several lactam analogues of this agent. These included 16 (1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one), 32 (the analogous quinolin-2-one), and 37 (the analogous benzazepin-2-one). The inotropic ED50's of these compounds were 24, 3.3, and 5.2 micrograms/kg, respectively, after iv administration to pentobarbital-anesthetized dogs. Compound 20 (LY195115, 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-i ndol-2- one), the geminal dimethyl analogue of 16, was 3.5-fold more potent than 16 when administered iv (ED50 = 6.8 micrograms/kg). However, the most profound effect of the geminal alkyl substitution was on oral activity. The approximate ED50's of 20 and 16 after oral administration to conscious dogs were 25 and 400 micrograms/kg, respectively. The increase in contractility produced by 25 micrograms/kg of 20 was maximally sustained in excess of 8 h. Thus, 20 is one of the most potent and long-acting oral inotropes described to date.

The cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3- pyridazinyl)-2H-indol-2-one (1, LY195115) is a potent, competitive inhibitor (Ki = 80 nM) of sarcoplasmic reticulum derived phosphodiesterase (SR-PDE). Moreover, the compound is a potent positive inotrope both in vitro and in vivo. To assist further cardiotonic drug-design studies, we have mapped the three-dimensional structure of 1 using X-ray crystallography. From a global viewpoint, this drug was essentially planar, but two small regions of nonplanarity were apparent. These involved the geminal methyl substituents in the indol-2-one moiety and the C5' methylene unit of the dihydropyridazinone ring. Because of our previous studies involving the bipyridine cardiotonics amrinone and milrinone, the conformational relationship between the plane of the phenyl ring and the horizontal symmetry plane defined by N2', C3', and C4' of 1 was of particular interest. The C6-C5-C3'-C4' dihedral angle was -2.7 degrees, whereas the C6-C5-C3'-N2' dihedral angle was 174.6 degrees. Therefore the two rings maintain a high degree of coplanarity. Compound 4, the congener of 1 possessing a completely unsaturated pyridazinone ring was also studied. In terms of inotropic activity, this compound, devoid of any puckering in the pyridazinone moiety, was equipotent with 1. Methyl substitution at the 4-position of the dihydropyridazinone and pyridazinone rings provided disparate results. Compound 2, the 4-methyl analogue of 1, was 2-fold more potent than 1, and the methyl substituent probably caused only minor perturbations in overall molecular topology. However 5, the 4-methyl analogue of the pyridazinone 4, was 4.4-fold less active than 4, perhaps as a result of methyl-induced molecular nonplanarity.