Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents.
In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC(50) = 7.0-8.7), whereas the pIC(50) values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30 micromol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.
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
Margaretha
M
Van der Mey
Kirsten M
KM
Bommelé
Hildegard
H
Boss
Armin
A
Hatzelmann
Mike
M
Van Slingerland
Geert J
GJ
Sterk
Hendrik
H
Timmerman
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016718:Arachidonic Acid; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C474580:4-(3,4-diethoxyphenyl)-2-(4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one; C474581:4-(3-chloro-4-methoxyphenyl)-2-(4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)butyl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D010793:Phthalazines; D011724:Pyridazines; D016718:Arachidonic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4