title: Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
abstract: We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
authors.affiliation: R&D Department, Laboratorios Menarini S.A., Alfonso XII 587, 08918, Badalona, Spain. apolomer-research@ferrergrupo.com
authors.forename: Albert
authors.initials: A
authors.lastname: Palomer
authors.forename: Jaume
authors.initials: J
authors.lastname: Pascual
authors.forename: Marta
authors.initials: M
authors.lastname: Cabré
authors.forename: Liset
authors.initials: L
authors.lastname: Borràs
authors.forename: Gracia
authors.initials: G
authors.lastname: González
authors.forename: Mònica
authors.initials: M
authors.lastname: Aparici
authors.forename: Assumpta
authors.initials: A
authors.lastname: Carabaza
authors.forename: Francesc
authors.initials: F
authors.lastname: Cabré
authors.forename: M Luisa
authors.initials: ML
authors.lastname: García
authors.forename: David
authors.initials: D
authors.lastname: Mauleón
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008565:Membrane Proteins; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases