Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues
M. Van Der Mey et al., Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues, J MED CHEM, 44(16), 2001, pp. 2511-2522
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.