6-Benzoxazinylpyridazin-3-ones: Potent, Long-Acting Positive Inotrope and Peripheral Vasodilator Agents

Article abstract of DOI:10.1021/jm00163a061

A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-<3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl>-2,3,4,5-tetrahydro-5-methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models.Additional benzoxazin-6-yl and -8-yl compounds were also prepared.Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED₅₀) from 77 to 5.4 μg/kg while substitution at the 8-position reduced potency.Methyl substitution at various sites in the molecule was also examined.Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 μg/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described.Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.