Chiral Dioxolane Inhibitors of Leukotriene Biosynthesis: Structure-Activity Relationships and Syntheses Using Asymmetric Dihydroxylation

Article abstract of DOI:10.1021/jm00020a008

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 0.039μM, 25-fold more potent than (R)-10d.In vivo, (S)-10d inhibited LTB₄ synthesis by 70percent 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 methoxytatrahydropyran series are related, a conclusion which can be supported by molecular modeling.