title: 1,2-Dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamides and congeners, dual cyclooxygenase/5-lipoxygenase inhibitors with antiinflammatory activity.
abstract: A series of 1,2-dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine, 1,2-dihydro-1-oxopyrrolo[3,2,1-kl]phenoxazine, and 1,2-dihydro-1-oxopyrrolo[3,2,1-de]acridine-2-carboxamides were prepared by reaction of 1,2-dihydro-1-oxo-pyrrolo[3,2,1-kl]phenothiazine 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-oxopyrrolo[3,2,1-kl]phenothiazine-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).
authors.affiliation: Pfizer Central Research, Groton, Connecticut 06340.
authors.forename: B L
authors.initials: BL
authors.lastname: Mylari
authors.forename: T J
authors.initials: TJ
authors.lastname: Carty
authors.forename: P F
authors.initials: PF
authors.lastname: Moore
authors.forename: W J
authors.initials: WJ
authors.lastname: Zembrowski
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors; D004487:Edema; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D011448:Prostaglandin Antagonists / Q000138:chemical synthesis*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D011448:Prostaglandin Antagonists; D011758:Pyrroles; D013843:Thiazines; D016718:Arachidonic Acid; D001091:Arachidonate Lipoxygenases