Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones

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).