Chiral dioxolane inhibitors of leukotriene biosynthesis: structure-activity relationships and syntheses using asymmetric dihydroxylation.
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.
Crawley
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GC
Vascular, Inflammatory and Muscular-Skeletal Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, United Kingdom.
Briggs
M T
MT
D000818:Animals; D004148:Dioxolanes / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004148:Dioxolanes; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4