Inotropic, vasodilator and low Km, cAMP-selective, cGMP-inhibited phosphodiesterase (PDE III) inhibitory activities of 4a-methyl-4,4a-dihydro-5H-indenopyridazin-3(2H)-ones and 4a-methyl-4,4a,5,6-tetrahydrobenzocinnolin-3(2H)-ones

Article abstract of DOI:10.1016/0223-5234(90)90196-A

Novel 7-substituted-4,4a-dihydro-4a-methyl-5H-indeno<1,2-c>pyridazin-3<2H>-ones and 8-substituted-4a-methyl-benzocinnolin-3<2H>-ones have been synthesized and their PDE III inhibitory, inotropic and vasodilator potencies compared with those of their normethyl analogues and their bicyclic 4,5-dihydro-6-phenylpyridazinone analogues.The structure-activity relationships of the tricyclic pyridazinones differ from those of bicyclic pyridazinones mainly in respect of the effect of introducing the methyl group into the pyridazinone ring.Whilst in the4,5-dihydro-6-phenylpyridazin-3(2H)-ones, introduction of a 5-methyl group has been widely reported to lead to compounds of significantly greater potency, the novel tricyclic 4a-methylpyridazinones showed similar levels of inotropic, vasodilator and PDE III inhibitory potency to their normethyl analogues.Possible reasons for this difference in behaviour are discussed.