title: Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.
abstract: 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.
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK. john.2.liddle@gsk.com
authors: John
authors: J
authors: Liddle
authors: Francis L
authors: FL
authors: Atkinson
authors: Michael D
authors: MD
authors: Barker
authors: Paul S
authors: PS
authors: Carter
authors: Neil R
authors: NR
authors: Curtis
authors: Rob P
authors: RP
authors: Davis
authors: Clement
authors: C
authors: Douault
authors: Marion C
authors: MC
authors: Dickson
authors: Dorothy
authors: D
authors: Elwes
authors: Neil S
authors: NS
authors: Garton
authors: Matthew
authors: M
authors: Gray
authors: Thomas G
authors: TG
authors: Hayhow
authors: Clare I
authors: CI
authors: Hobbs
authors: Emma
authors: E
authors: Jones
authors: Stuart
authors: S
authors: Leach
authors: Karen
authors: K
authors: Leavens
authors: Huw D
authors: HD
authors: Lewis
authors: Scott
authors: S
authors: McCleary
authors: Margarete
authors: M
authors: Neu
authors: Vipulkumar K
authors: VK
authors: Patel
authors: Alex G S
authors: AG
authors: Preston
authors: Cesar
authors: C
authors: Ramirez-Molina
authors: Tracy J
authors: TJ
authors: Shipley
authors: Philip A
authors: PA
authors: Skone
authors: Nick
authors: N
authors: Smithers
authors: Donald O
authors: DO
authors: Somers
authors: Ann L
authors: AL
authors: Walker
authors: Robert J
authors: RJ
authors: Watson
authors: Gordon G
authors: GG
authors: Weingarten
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001183:Arthus Reaction / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
chemical_list: D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; C585067:GSK143; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat