Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents

Margaretha Van der Mey; Kirsten M Bommelé; Hildegard Boss; Armin Hatzelmann; Mike Van Slingerland; Geert J Sterk; Hendrik Timmerman

doi:10.1021/jm030776l

Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents

J Med Chem. 2003 May 8;46(10):2008-16. doi: 10.1021/jm030776l.

Authors

Margaretha Van der Mey¹, Kirsten M Bommelé, Hildegard Boss, Armin Hatzelmann, Mike Van Slingerland, Geert J Sterk, Hendrik Timmerman

Affiliation

¹ 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

PMID: 12723963
DOI: 10.1021/jm030776l

Abstract

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.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Arachidonic Acid
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4
Edema / chemically induced
Edema / drug therapy
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Mice
Phthalazines / chemical synthesis*
Phthalazines / chemistry
Phthalazines / pharmacology
Pyridazines / chemical synthesis*
Pyridazines / chemistry
Pyridazines / pharmacology
Structure-Activity Relationship

Substances

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
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
Anti-Inflammatory Agents, Non-Steroidal
Enzyme Inhibitors
Phthalazines
Pyridazines
Arachidonic Acid
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4