1,2-Dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamides and congeners, dual cyclooxygenase/5-lipoxygenase inhibitors with anti-inflammatory activity
| Autor: | Thomas J. Carty, Peter F. Moore, Banavara L. Mylari, William James Zembrowski |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Male
Models Molecular Magnetic Resonance Spectroscopy Prostaglandin Antagonists medicine.drug_class Thiazines Carboxamide Arachidonic Acids Pharmacology Arachidonate Lipoxygenases Mass Spectrometry Cell Line Structure-Activity Relationship chemistry.chemical_compound Lipoxygenase Phenothiazine Drug Discovery medicine Animals Edema Cyclooxygenase Inhibitors Pyrroles Lipoxygenase Inhibitors Arachidonic Acid Molecular Structure biology Chemistry Anti-Inflammatory Agents Non-Steroidal Rats Inbred Strains Rats Enzyme inhibitor Arachidonate 5-lipoxygenase biology.protein Molecular Medicine Indicators and Reagents Arachidonic acid Cyclooxygenase Phenoxazine |
| Zdroj: | Journal of Medicinal Chemistry. 33:2019-2024 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00169a035 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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