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]acetanilid ((S)-10d) inhibited leukotriene B-4 (LTB(4)) synthesis in A23187-stimulated human whole blood in vitro with IC50 0.039 mu M, 25-fold more potent than (R)-10d. In vivo, (S)-10d inhibited LTB(4) 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.