STUDIES ON 5-LIPOXYGENASE INHIBITORS - II - DISCOVERY, OPTICAL RESOLUTION AND ENANTIOSELECTIVE SYNTHESIS OF FR110302, A HIGHLY POTENT NONREDOX TYPE 5-LIPOXYGENASE INHIBITOR

A novel series of (2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthols w as synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Syst ematic optimization led to identification of several highly potent non -redox type 5-LO inhibitors with nanomolar IC(50)s as racemic mixtures . Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer, An effici ent synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, -(2-quino lylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (FR110302, (+)-50), showed p otent inhibitory activity against leukotriene (LT) biosynthesis by int act neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM), Fur thermore oral administration of FR110302 significantly inhibited neutr ophil migration in the rat air pouch model at 1 mg/kg.