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. Results & discussion: 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. Conclusion: This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Acknowledgements
We are grateful to CEM (Microwave Technology) Ltd (Buckinghamshire, UK), in particular David Lofty and Chris Mason, for technical assistance and the use of Voyager apparatus in our laboratories.
Financial & competing interests disclosure
This work was supported by the Engineering and Physical Sciences Research Council (GR/S25456 to Mark Bagley, with additional DTA support for Vincenzo Fusillo), the Biotechnology and Biological Sciences Research Council (BB/D524140/1 to David Kipling, Mark Bagley and Terence Davis) and Strategic Promotion of Ageing Research Capacity (awards to Mark Bagley and Terence Davis). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.