Effect of Structural Modification of Enol−Carboxamide-Type Nonsteroidal Antiinflammatory Drugs on COX-2/COX-1 Selectivity

TLDR

Meloxicam (5), an enol‑carboxamide NSAID, was developed for its anti‑inflammatory activity and relative safety in animal models. The study aimed to determine whether structural modifications of enol‑carboxamide compounds could markedly enhance COX‑2 selectivity and potency. We examined substitutions at the 6‑ and 7‑positions of the 4‑oxo‑1,2‑benzothiazine‑3‑carboxamide core, altered the N‑methyl group, modified the amide, and explored related isomeric and heterocyclic analogues such as 3‑oxo‑1,2‑benzothiazine‑4‑carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3‑/1,4‑dioxoisoquinolines. Although a few analogues showed higher COX‑2 potency, none surpassed meloxicam (5) in COX‑2/COX‑1 selectivity.

Abstract

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, indolothiazines, 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.