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Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1.


C I Bayly, W C Black, S Léger, N Ouimet, M Ouellet, M D Percival. Structure-based design of COX-2 selectivity into flurbiprofen. Bioorganic & medicinal chemistry letters. 1999 Feb 8;9(3):307-12

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PMID: 10091674

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