title: Structure-based design of COX-2 selectivity into flurbiprofen.
abstract: 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.
authors: Merck Frosst Canada Inc., Pointe-Claire-Dorval, Quebec, Canada.
authors: C I
authors: CI
authors: Bayly
authors: W C
authors: WC
authors: Black
authors: S
authors: S
authors: Léger
authors: N
authors: N
authors: Ouimet
authors: M
authors: M
authors: Ouellet
authors: M D
authors: MD
authors: Percival
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D005480:Flurbiprofen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases