Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimi- dinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors Martin E. Swarbrick §§ , Paul J. Beswick   , Robert J. Gleave * , Richard H. Green, Sharon Bingham, Chas Bountra   , Malcolm C. Carter à , Laura J. Chambers, Iain P. Chessell § , Nick M. Clayton, Sue D. Collins, John A. Corfield, C. David Hartley – , Savvas Kleanthous, Paul F. Lambeth, Fiona S. Lucas, Neil Mathews à , Alan Naylor, Lee W. Page, Jeremy J. Payne, Neil A. Pegg || , Helen S. Price, John Skidmore, Alexander J. Stevens, Richard Stocker, Sharon C. Stratton, Alastair J. Stuart    , Joanne O. Wiseman Pain and Neuroexcitability Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK article info Article history: Received 28 November 2008 Revised 20 February 2009 Accepted 22 February 2009 Available online 26 February 2009 Keywords: Cyclooxygenase COX-2 Pyrimidine CNS penetrant abstract A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygen- ase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more com- mon 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4- (methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity. Ó 2009 Elsevier Ltd. All rights reserved. The demonstration that early selective inhibitors of cyclooxy- genase-2 (COX-2), such as DuP697 (1) 1 and SC 58125 (2, Fig. 1), 2 could produce analgesic effects in preclinical models that was not accompanied by the typical gastrointestinal toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspi- rin and indomethacin provoked intense interest in the area, and several groups have since reported potent and selective COX-2 inhibitors. The clinical promise of this class has been fulfilled by 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.02.085 * Corresponding author. Tel.: +44 1279 643079. E-mail address: robert.j.gleave@gsk.com (R.J. Gleave).   Present address: Structural Genomics Consortium (SGC), University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK. à Present address: Arrow Therapeutics, Britannia House, 7 Trinity Street, London SE1 1DA, UK. § Present address: MedImmune, Milstein Building, Granta Park, Cambridge CB21 6GH, UK. – Present address: BioFocus DPI, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK. || Present address: CellCentric Ltd, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, UK.    Present address: Takeda Global Research and Development Centre Europe Ltd., 61 Aldwych, London WC2B 4AE, UK. §§ Discovery Laboratory, Cancer Research Technology Ltd., 12 Rosemary Lane, Cambridge CB1 3LQ, UK. S Br F MeO 2 S N N F MeO 2 S CF 3 1, DuP697 2, SC 58125 N N Me H 2 NO 2 S CF 3 N MeO 2 S N Me Cl 3, Celecoxib 4, Etoricoxib MeO 2 S EtO N N N MeO 2 S N N NR 1 R 2 CF 3 5, GW406381 6 Figure 1. Bioorganic & Medicinal Chemistry Letters 19 (2009) 4504–4508 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl