Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4504-8. doi: 10.1016/j.bmcl.2009.02.085.
Martin E Swarbrick  1 ,  Paul J Beswick ,  Robert J Gleave ,  Richard H Green ,  Sharon Bingham ,  Chas Bountra ,  Malcolm C Carter ,  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 ,  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
Affiliations
  • 1. 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.
PMID: 19520573 DOI: 10.1016/j.bmcl.2009.02.085
Abstract

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 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.