title: Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models.
abstract: In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal antiinflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290 degrees +/- 10 degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor 8a. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.
authors.affiliation: R&D Department, Laboratorios Menarini S.A., Alfonso XII 587, 08918 Badalona, Spain. apalomer-research@ferrergrupo.com
authors.forename: Albert
authors.initials: A
authors.lastname: Palomer
authors.forename: Francesc
authors.initials: F
authors.lastname: Cabré
authors.forename: Jaume
authors.initials: J
authors.lastname: Pascual
authors.forename: Joaquín
authors.initials: J
authors.lastname: Campos
authors.forename: María A
authors.initials: MA
authors.lastname: Trujillo
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Lluïsa
authors.initials: L
authors.lastname: García
authors.forename: David
authors.initials: D
authors.lastname: Mauleón
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D000068579:Celecoxib; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D007783:Lactones / Q000494:pharmacology*; D008565:Membrane Proteins; D008956:Models, Chemical; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; C102643:SC 558; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin