title: Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core.
abstract: A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Pakornwit
authors.initials: P
authors.lastname: Sarnpitak
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mujumdar
authors.affiliation: Department of Entomology, University of California, One Shields Avenue, Davis, CA 95616-8584, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology, University of California, One Shields Avenue, Davis, CA 95616-8584, United States.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Entomology, University of California, One Shields Avenue, Davis, CA 95616-8584, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hammock
authors.affiliation: Enamine Ltd, 78 Chervonotkatska Street, Kyiv 02094, Ukraine.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Iurchenko
authors.affiliation: Enamine Ltd, 78 Chervonotkatska Street, Kyiv 02094, Ukraine.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zozulya
authors.affiliation: School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Antonis
authors.initials: A
authors.lastname: Gavalas
authors.affiliation: School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Geronikaki
authors.affiliation: Moscow Institute of Physics & Technology (State University) Dolgoprudny, Moscow Region 141700, Russia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ivanenkov
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; Department of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russia. Electronic address: m.krasavin@hotmail.com.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D002351:Carrageenan; C017424:2-imidazoline; D051546:Cyclooxygenase 2
keywords: Amidines; Anti-inflammatory; Blood–brain barrier; Coxibs; High-sp3; Mouse paw edema; Non-aromatic