Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity
| Autor: | Sorcek Ronald J, Simon J. Coutts, L. Churchill, Eva David, Mcneil Daniel W, Gunter Trummlitz, Hin-Chor Wong, Peter M. Grob, Ian Potocki, Hans Meier, Matt Aaron Tschantz, Wolfhard Engel, Lazer Edward S, Miao Clara K, A. G. Graham, Terence A. Kelly, Charles L. Cywin, Maryann Hoermann, Zhaoxing Meng, Roger J. Snow |
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| Rok vydání: | 1997 |
| Předmět: |
Magnetic Resonance Spectroscopy
medicine.drug_class Stereochemistry Thiazines Carboxamide Pharmacology Piroxicam Meloxicam Chemical synthesis Substrate Specificity Structure-Activity Relationship Drug Discovery medicine Potency Structure–activity relationship Humans Cyclooxygenase Inhibitors biology Cyclooxygenase 2 Inhibitors Molecular Structure Chemistry Anti-Inflammatory Agents Non-Steroidal Membrane Proteins Recombinant Proteins Isoenzymes Thiazoles Enzyme inhibitor Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases biology.protein Cyclooxygenase 1 Molecular Medicine Selectivity medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 40(6) |
| ISSN: | 0022-2623 |
| Popis: | Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5. |
| Databáze: | OpenAIRE |
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