title: Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome.
abstract: BACKGROUND
  The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use.
  
  
  CONCLUSIONS
  Microwave irradiation using a stop-flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C-S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield.
  
  
  CONCLUSIONS
  This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.
authors.affiliation: School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK. bagleymc@cardiff.ac.uk
authors.forename: Mark C
authors.initials: MC
authors.lastname: Bagley
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Dix
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fusillo
authors.forename: Morgane
authors.initials: M
authors.lastname: Pigeaux
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Rokicki
authors.forename: David
authors.initials: D
authors.lastname: Kipling
mesh_terms: D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization; D014898:Werner Syndrome / Q000188:drug therapy*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745