Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease

  • Bioorg Med Chem Lett. 2018 Nov 15;28(21):3458-3462. doi: 10.1016/j.bmcl.2018.09.022.
Michael D Barker  1 ,  John Liddle  2 ,  Francis L Atkinson  2 ,  David Matthew Wilson  2 ,  Marion C Dickson  2 ,  Cesar Ramirez-Molina  2 ,  Huw Lewis  2 ,  Rob P Davis  2 ,  Donald O Somers  2 ,  Margarete Neu  2 ,  Emma Jones  2 ,  Robert Watson  2
Affiliations
  • 1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: [email protected].
  • 2. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
PMID: 30249354 DOI: 10.1016/j.bmcl.2018.09.022
Abstract

The discovery and lead optimisation of a novel series of Syk inhibitors is described. These were optimised for Syk potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

Keywords
Dermal; Inhibitor; Lead optimisation; SYK; Skin penetration; Spleen Tyrosine Kinase.
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