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A series of 1,2-dihydro-1-oxopyrrolo3,2,1-klphenothiazine, 1,2-dihydro-1-oxopyrrolo3,2,1-klphenoxazine, and 1,2-dihydro-1-oxopyrrolo3,2,1-deacridine-2-carboxamides were prepared by reaction of 1,2-dihydro-1-oxo-pyrrolo3,2,1-klphenothiazine or other corresponding phenoxazine and acridan ethyl or methyl esters with appropriate amines. Several members of this family were found to be potent, dual inhibitors of cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism and to have in vivo antiinflammatory activity in the rat foot edema assay. Structure-activity relationships within this family of compounds are described. 1,2-Dihydro-N-(2-thiazolyl)-1-oxopyrrolo3,2,1-klphenothiazine-1- carboxamide (34) was found to be one of the best compounds to display potent cyclooxygenase/5-lipoxygenase inhibition of arachidonic acid metabolism. Its IC50s against the enzymes sourced from rat basophillic leukemia-1 (RBL-1) cells were 0.07 and 1.4 microM, respectively. It was active in the rat foot edema test for antiinflammatory effect (48% inhibition at 33 mg/kg po) and in the mouse phenylbenzoquinone induced writhing test for analgesic effect (93% inhibition at 32 mg/kg po).
Mylari et al. (Sun,) studied this question.