Dihydropyridazinone cardiotonics. The discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one

Abstract

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.

Specific binding of [3H]LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles.

“…Indolidan and milrinone (1 jiM) also produced nearly complete displacement of bound radiolabel. By contrast, propranolol, prazosin, and nifedipine had little or no effect at the concentration of 1 Discussion LY 186126 was previously shown to be equipotent to indolidan as a positive inotropic agent in 10 In the present report, LY186126 was found to be a potent inhibitor of SR-PDE. Based on the observed IQo of 0.12 fiM, LY186126 was equipotent to indolidan (IC^O.13 /uM) 2 as an inhibitor of SR-PDE.…”

“…9 The radiolabeled drug was highly stable and the radiochemical purity was 99.8% after 1 year of storage at -20° C in ethanol (data not shown). The synthesis and characterization of indolidan and LY186126 were as described in the literature 10 onstrated that BSA had no effect on specific binding to SR vesicles (data not shown). Furthermore, specific binding was abolished by the following: removal of Mg 24 from the binding medium, boiling the membranes for 1 minute, or subjecting membranes to proteolysis with trypsin (data not shown).…”

The Emergence of Multiple Coordination Numbers in Gold–Cyanoarene Complexes: A Study of the On-Surface Coordination Mechanism

“…To enhance the surface mobility of the ligand so that it can undergo an on-surface coordination reaction with a single Au adatom, two dimethyl groups were attached to the indoline ring, as shown in Scheme . These methyl groups prevent IBN from adsorbing strongly onto the Au(111) surface. − IBN was synthesized by nucleophilic aromatic substitution of 3,3-dimethylindoline , by 4-fluorobenzonitrile in 43% yield (Scheme ; see also Scheme S1 in the Supporting Information). The indoline group can rotate around the N­(indoline)–C­(phenyl) bond axis to form two types of surface-induced chiralities of the ligand.…”

The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function

“…A range of dihydropyridazinones have been described in the literature as cGI-PDE inhibitors in which the activity is enhanced by the presence of a 5-methyl substituent in the dihydropyridazinone ring (e.g. Robertson et al, 1986). Such compounds are chiral due to the asymmetric carbon at the 5-position and, for the first time, we present detailed results which show that the R-enantiomer is the active form for both biochemical and pharmacological action.…”