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

DOI: 10.1016/j.bmcl.2018.09.022 DOI Help

Authors: Michael D. Barker (GlaxoSmithKline R&D) , John Liddle (GlaxoSmithKline R&D) , Francis L. Atkinson (GlaxoSmithKline R&D) , David Matthew Wilson (GlaxoSmithKline R&D) , Marion C. Dickson (GlaxoSmithKline R&D) , Cesar Ramirez-molina (GlaxoSmithKline R&D) , Huw Lewis (GlaxoSmithKline R&D) , Rob P. Davis (GlaxoSmithKline R&D) , Donald O. Somers (GlaxoSmithKline R&D) , Margarete Neu (GlaxoSmithKline R&D) , Emma Jones (GlaxoSmithKline R&D) , Robert Watson (GlaxoSmithKline R&D)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 28 , PAGES 3458 - 3462

State: Published (Approved)
Published: November 2018

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.

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

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography