INOTROPIC, VASODILATOR AND LOW KM, CAMP-SELECTIVE, CGMP-INHIBITED PHOSPHODIESTERASE (PDE III) INHIBITORY ACTIVITIES OF 4-ALPHA-METHYL-4,4-ALPHA-DIHYDRO-5H-INDENO[1,2-C]PYRIDAZIN-3(2H)-ONES AND 4-ALPHA-METHYL-4,4-ALPHA,5,6-TETRAHYDROBENZO[H]CINNOLIN-3(2H)-ONES

Novel 7-substituted-4,4a-dihydro-4a-methyl-5H-indenol[1,2-c]pyridazin-3[2H]-ones and 8-substituted-4a-methylbenzo[h]cinnolin-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 the 4,5-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.