M. Van Der Mey et al., Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones, J MED CHEM, 44(16), 2001, pp. 2523-2535
A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-h
exahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-spe
cific phosphodiesterase (PDE4) was synthesized. To study structure-activity
relationships various substituents were introduced to the 2-, 3-, and 4-po
sitions of the 4-phenyl ring. Substitution at the 4-position of the phenyl
ring was restricted to a methoxy group, probably due to unfavorable steric
interactions of larger groups with the binding site. The introduction of ma
ny alkoxy substituents including distinct ring systems and functional group
s was allowed to the 3-position. It was found that in general the cis-4a,5,
8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydroph
thalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy
)butoxy analogue 16o (pIC(50) = 9.7).