Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues

A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a n ovel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared a nd tested on the eGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specif ically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In bot h the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it a lso accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a, 5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrah ydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7 .6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e )ne rings occupy a region in space different from that occupied by the othe r fused (un)saturated hydrocarbon rings applied; we therefore assume that t he steric interactions of these rings with the binding site play an importa nt role in enzyme inhibition.