Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones

Margaretha Van der Mey; Hildegard Boss; Armin Hatzelmann; Ivonne J Van der Laan; Geert J Sterk; Hendrik Timmerman

doi:10.1021/jm0110340

Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones

J Med Chem. 2002 Jun 6;45(12):2520-5. doi: 10.1021/jm0110340.

Authors

Margaretha Van der Mey¹, Hildegard Boss, Armin Hatzelmann, Ivonne J Van der Laan, Geert J Sterk, Hendrik Timmerman

Affiliation

¹ Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1085c, 1081 HV Amsterdam, The Netherlands. mmeij@rnc.vu.nl

PMID: 12036360
DOI: 10.1021/jm0110340

Abstract

The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFalpha release and show moderate potency against fMLP-stimulated production of ROS.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Adamantane / analogs & derivatives
Adamantane / chemical synthesis
Adamantane / chemistry
Adamantane / pharmacology
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4
Cycloheptanes / chemical synthesis
Cycloheptanes / chemistry
Cycloheptanes / pharmacology
Edema / drug therapy
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Female
Humans
In Vitro Techniques
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Lipopolysaccharides / pharmacology
Luminescent Measurements
Mice
Phthalazines / chemical synthesis*
Phthalazines / chemistry
Phthalazines / pharmacology
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cycloheptanes
Enzyme Inhibitors
Lipopolysaccharides
Phthalazines
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4
Adamantane