Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones.

Abstract

Recently, we reported that 4-catechol-substituted cis-(+/-)-4a,5,6,7,8,8a-hexa- and cis-(+/-)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting materials, were resolved in a classical way by the formation of diastereomeric salts, and each was converted to optically active phthalazinone in an enantioselective manner. The absolute configuration of the (+)-enantiomer of cis-hexahydrophthalazinone (+)-12 was determined by X-ray crystallography. The carbon atoms at the 4a and 8a positions were found to have the S- and R-configuration, respectively. In the present series of hexa- and tetrahydrophthalazinones, stereoselectivity for PDE4 inhibition is observed; the cis-(+)-enantiomers of the phthalazinones display high inhibitory activity, whereas their (-)-counterparts exhibit only weak to moderate activity. It is likely that all cis-(+)-phthalazinones have a (4aS,8aR)-configuration and vice versa for the cis-(-)-analogues. In the current series, the N-adamantan-2-yl analogue (+)-14 shows the most potent inhibition of PDE4 (pIC(50) = 9.3); the corresponding (-)-enantiomer is 250-fold less active. In addition, the N-substituted tetrahydrophthalazinones under study were investigated for their in vivo antiinflammatory activities by examining the suppression of arachidonic acid (AA) induced mouse ear edema formation. In this assay analogues (+)-14 and (+)-15 were found to be potent antiinflammatory agents showing about 50% inhibition at 30 micromol/kg po.

• Authors: Margaretha Van der Mey, Hildegard Boss, Dennis Couwenberg, Armin Hatzelmann, Geert J Sterk, Kees Goubitz, Henk Schenk, Hendrik Timmerman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 12 Pg. 2526-33 (Jun 06 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12036361 (Publication Type: Journal Article)

Chemical References

• 2-adamantan-2-yl-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
• 4-(4-(3,4-diethoxyphenyl)-1oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl)benzoic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Benzoates
• Enzyme Inhibitors
• Phthalazines
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Adamantane

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors)
• Adamantane (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Benzoates (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Edema (drug therapy)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• In Vitro Techniques
• Mice
• Molecular Conformation
• Neutrophils (drug effects, enzymology)
• Phthalazines (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship