EFFECT OF STRUCTURAL MODIFICATION OF ENOL-CARBOXAMIDE-TYPE NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON COX-2 COX-1 SELECTIVITY/

Meloxicam (5), an NSAID in the enol-carboxamide class, was developed o n the basis of its antiinflammatory activity and relative safety in an imal 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 therefo re embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by st ructural modification. Substitution at the 6- and 7-positions of the 4 -oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl subst ituent, and amide modification were all examined. In addition we explo red several related systems including the isomeric 3-oxo-1,2-benzothia zine-4-carboxamides, thienothiazines, indolothiazines, benzothienothia zines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no co mpound tested had a better COX-2/COX-1 selectivity profile than that o f 5.