STUDIES ON 5-LIPOXYGENASE INHIBITORS - II - DISCOVERY, OPTICAL RESOLUTION AND ENANTIOSELECTIVE SYNTHESIS OF FR110302, A HIGHLY POTENT NONREDOX TYPE 5-LIPOXYGENASE INHIBITOR
T. Yatabe et al., STUDIES ON 5-LIPOXYGENASE INHIBITORS - II - DISCOVERY, OPTICAL RESOLUTION AND ENANTIOSELECTIVE SYNTHESIS OF FR110302, A HIGHLY POTENT NONREDOX TYPE 5-LIPOXYGENASE INHIBITOR, Chemical and Pharmaceutical Bulletin, 46(10), 1998, pp. 1556-1565
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.