Template substituent position

It is assumed that the heterocyclic core structure is responsible for the appropriate orientation of the aromatic rings in space and finally for binding to the enzyme. A wide variety of heterocycles can serve as templates, i.e. pyrrole, thiazole, oxazole furane, furanone, imidazole, isoxazole, pyrimidine and thiophene, but at the moment pyrazole and cylopentenone seem to be the most appropriate for achieving COX-2 specificity. For optimal activity, one aromatic ring must be substituted with a methylsulfonyl or a sulfonamide substituent in the para position. Substitution at position 4 of one of the aromatic systems with a sulfonamide or a methylsulfonyl group is essential for COX inhibition. Replacement of the methylsulfonyl group by a sulfonamide group reduces COX-2 selectivity but improves oral bioavailability. 

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