STUDIES ON 5-LIPOXYGENASE INHIBITORS - I - SYNTHESIS AND 5-LIPOXYGENASE-INHIBITORY ACTIVITY OF NOVEL HYDROXAMIC ACID-DERIVATIVES

A series of novel hydroxamates has been prepared and tested for inhibi tory activity towards rat polymorphonuclear leukocyte (PMN) 5-lipoxyge nase (5-LO) in vitro and towards neutrophil migration in the rat air p ouch model of inflammation in vivo, Many 3,4-dihydronaphthyl compounds were potent inhibitors of 5-LO, and several compounds were potent inh ibitors of neutrophil migration, The most potent 3,4-dihydronaphthyl c ompound, phenoxy)-2-naphthyl]methyl]-N-hydroxy-N'-ethylurea (FR122788, 18) had an IC50 of 25 nM in the 5-LO assay, and strongly reduced neut rophil migration in the rat air pouch model at 1 mg/kg (p.o.). FR12278 8 also had an ameliorating effect in a rat hepatiatis model induced by D-galactosamine, with an ED50 values of 14.6 mg/kg (p.o.) for glutama te oxaloacetate transaminase (GOT) and 16.8 mg/kg (p.o.) for glutamate pyruvate transaminase (GPT).