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

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

E S Lazer, C K Miao, C L Cywin, R Sorcek, H C Wong, Z Meng, I Potocki, M Hoermann, R J Snow, M A Tschantz, T A Kelly, D W McNeil, S J Coutts, L Churchill, A G Graham, E David, P M Grob, W Engel, H Meier, etc.

J Med Chem. 1997 Mar 14;40(6):980-9.

PMID: 9083488

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, 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP24683269	Meloxicam Related Compound A		24683-26-9	Price

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