Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor
2011
Liddle, John | Atkinson, Francis L. | Barker, Michael D. | Carter, Paul S. | Curtis, Neil R. | Davis, Rob P. | Douault, Clement | Dickson, Marion C. | Elwes, Dorothy | Garton, Neil S. | Gray, Matthew | Hayhow, Thomas G. | Hobbs, Clare I. | Jones, Emma | Leach, Stuart | Leavens, Karen | Lewis, Huw D. | McCleary, Scott | Neu, Margarete | Patel, Vipulkumar K. | Preston, Alex G.S. | Ramirez-Molina, Cesar | Shipley, Tracy J. | Skone, Philip A. | Smithers, Nick | Somers, Donald O. | Walker, Ann L. | Watson, Robert J. | Weingarten, Gordon G.
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
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