Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones
| Autor: | Hildegard Boss, Ivonne J. Van Der Laan, Hendrik Timmerman, Geert Jan Sterk, Armin Hatzelmann, Margaretha Van Der Mey |
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| Rok vydání: | 2002 |
| Předmět: |
Lipopolysaccharides
Stereochemistry Administration Oral Adamantane In Vitro Techniques Chemical synthesis Mice Structure-Activity Relationship In vivo Oral administration Drug Discovery Animals Edema Humans Potency Cycloheptanes Enzyme Inhibitors chemistry.chemical_classification Bicyclic molecule biology Tumor Necrosis Factor-alpha Chemistry Anti-Inflammatory Agents Non-Steroidal Cyclic Nucleotide Phosphodiesterases Type 3 In vitro Cyclic Nucleotide Phosphodiesterases Type 4 Enzyme 3' 5'-Cyclic-AMP Phosphodiesterases Enzyme inhibitor Luminescent Measurements Leukocytes Mononuclear biology.protein Phthalazines Molecular Medicine Female Reactive Oxygen Species |
| Zdroj: | Journal of Medicinal Chemistry. 45:2520-2525 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0110340 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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