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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
20
|
| pubmed:dateCreated |
1995-11-8
|
| pubmed:abstractText |
1,3-Dioxolanes have been described as chiral inhibitors of 5-lipoxygenase (5LO). In the present work, this series has been developed further to provide agents which showed comparable or superior potency in vivo to ZD2138, a methoxytetrahydropyran inhibitor of 5LO, which is currently undergoing clinical evaluation. An asymmetric synthesis was developed to these dioxolanes based on asymmetric dihydroxylation. (S)-N-Methyl-4'-[[4-(2,2,4- trimethyl-1,3-dioxolan-4-yl)thien-2-yl]thio]acetanilide ((S)-10d) inhibited leukotriene B4 (LTB4) synthesis in A23187-stimulated human whole blood in vitro with IC50 0.039 microM, 25-fold more potent than (R)-10d. In vivo, (S)-10d inhibited LTB4 synthesis by 70% in zymosan-inflamed air pouch exudate in rat 10 h after an oral dose of 1.5 mg/kg. Structure-activity relationship considerations suggested that the dioxolane and methoxytetrahydropyran series are related, a conclusion which can be supported by molecular modeling.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Sep
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
29
|
| pubmed:volume |
38
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3951-6
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading | |
| pubmed:year |
1995
|
| pubmed:articleTitle |
Chiral dioxolane inhibitors of leukotriene biosynthesis: structure-activity relationships and syntheses using asymmetric dihydroxylation.
|
| pubmed:affiliation |
Vascular, Inflammatory and Muscular-Skeletal Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, United Kingdom.
|
| pubmed:publicationType |
Journal Article
|