Linked Life Data

12036361

Source:http://linkedlifedata.com/resource/pubmed/id/12036361

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2002-5-30
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
6
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2526-33
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12036361-3',5'-Cyclic-AMP Phosphodiesterases, pubmed-meshheading:12036361-Adamantane, pubmed-meshheading:12036361-Administration, Oral, pubmed-meshheading:12036361-Animals, pubmed-meshheading:12036361-Anti-Inflammatory Agents, Non-Steroidal, pubmed-meshheading:12036361-Benzoic Acids, pubmed-meshheading:12036361-Crystallography, X-Ray, pubmed-meshheading:12036361-Cyclic Nucleotide Phosphodiesterases, Type 4, pubmed-meshheading:12036361-Edema, pubmed-meshheading:12036361-Enzyme Inhibitors, pubmed-meshheading:12036361-Female, pubmed-meshheading:12036361-Humans, pubmed-meshheading:12036361-Mice, pubmed-meshheading:12036361-Molecular Conformation, pubmed-meshheading:12036361-Neutrophils, pubmed-meshheading:12036361-Phthalazines, pubmed-meshheading:12036361-Stereoisomerism, pubmed-meshheading:12036361-Structure-Activity Relationship
pubmed:year
2002
pubmed:articleTitle
Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones.
pubmed:affiliation
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
pubmed:publicationType
Journal Article, In Vitro