title: 6-Benzoxazinylpyridazin-3-ones: potent, long-acting positive inotrope and peripheral vasodilator agents.
abstract: 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 micrograms/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 micrograms/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.
authors: R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869.
authors: D W
authors: DW
authors: Combs
authors: M S
authors: MS
authors: Rampulla
authors: S C
authors: SC
authors: Bell
authors: D H
authors: DH
authors: Klaubert
authors: A J
authors: AJ
authors: Tobia
authors: R
authors: R
authors: Falotico
authors: B
authors: B
authors: Haertlein
authors: C
authors: C
authors: Lakas-Weiss
authors: J B
authors: JB
authors: Moore
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D048588:Benzoxazines; D002316:Cardiotonic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D048588:Benzoxazines; D002316:Cardiotonic Agents; D010078:Oxazines; D011724:Pyridazines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C062457:bemoradan