title: In situ click chemistry generation of cyclooxygenase-2 inhibitors.
abstract: Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.
authors.affiliation: Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada, T6G 1Z2.|Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta, 8613-114 Street, Edmonton, Alberta, Canada, T6G 2H7.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada, T6G 1Z2.|Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta, 8613-114 Street, Edmonton, Alberta, Canada, T6G 2H7.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada, T6G 1Z2.
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.affiliation: Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada, T6G 1Z2. wuest@ualberta.ca.|Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta, 8613-114 Street, Edmonton, Alberta, Canada, T6G 2H7. wuest@ualberta.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D057930:Click Chemistry / Q000379:methods*; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006614:Hindlimb; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D014230:Triazoles; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2