title: Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones.
abstract: A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions 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 many alkoxy substituents including distinct ring systems and functional groups 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 hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC(50) = 9.7).
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. mmeij@rnc.vu.nl
authors.forename: M
authors.initials: M
authors.lastname: Van der Mey
authors.forename: A
authors.initials: A
authors.lastname: Hatzelmann
authors.forename: G P
authors.initials: GP
authors.lastname: Van Klink
authors.forename: I J
authors.initials: IJ
authors.lastname: Van der Laan
authors.forename: G J
authors.initials: GJ
authors.lastname: Sterk
authors.forename: U
authors.initials: U
authors.lastname: Thibaut
authors.forename: W R
authors.initials: WR
authors.lastname: Ulrich
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009504:Neutrophils / Q000201:enzymology; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D020889:Rolipram / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram