RESUMEN
A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.
Asunto(s)
Cardiotónicos/síntesis química , Oxazinas/química , Oxazinas/síntesis química , Piridazinas/química , Piridazinas/síntesis química , Animales , Benzoxazinas , Cardiotónicos/química , Cardiotónicos/farmacología , Perros , Corazón/efectos de los fármacos , Miocardio/enzimología , Oxazinas/farmacología , Piridazinas/farmacología , Relación Estructura-ActividadRESUMEN
A synthetic program of rational drug design was undertaken to develop a series of quinazoline-3-oxides as pulmonary-selective inhibitors of ovalbumin-induced, leukotriene-mediated bronchoconstriction. The most active and selective compounds contained a methyl group at the 4-position, a medium sized branched alkyl group at the 2-position, and a small electron donating group on the phenyl ring. Significant enhancement in selectivity was observed in comparing the pulmonary versus cardiovascular effects of these new bronchodilators with the effects of theophylline.
Asunto(s)
Broncodilatadores/síntesis química , Quinazolinas/síntesis química , Animales , Espasmo Bronquial/inducido químicamente , Espasmo Bronquial/prevención & control , Broncodilatadores/química , Broncodilatadores/farmacología , Perros , Diseño de Fármacos , Femenino , Cobayas , Hemodinámica/efectos de los fármacos , Leucotrienos/fisiología , Espectroscopía de Resonancia Magnética , Masculino , Ovalbúmina/inmunología , Pilocarpina/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Teofilina/farmacologíaRESUMEN
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.