title: Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.
abstract: The optimisation of the azanaphthyridine 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 hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. Electronic address: Neil.S.Garton@gsk.com.
authors: Neil S
authors: NS
authors: Garton
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Michael D
authors: MD
authors: Barker
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Rob P
authors: RP
authors: Davis
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Clement
authors: C
authors: Douault
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Edward
authors: E
authors: Hooper-Greenhill
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Emma
authors: E
authors: Jones
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Huw D
authors: HD
authors: Lewis
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: John
authors: J
authors: Liddle
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Dave
authors: D
authors: Lugo
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Scott
authors: S
authors: McCleary
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Alex G S
authors: AGS
authors: Preston
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Cesar
authors: C
authors: Ramirez-Molina
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Margarete
authors: M
authors: Neu
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Tracy J
authors: TJ
authors: Shipley
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Don O
authors: DO
authors: Somers
authors: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors: Robert J
authors: RJ
authors: Watson
authors: AstraZeneca, Hodgkin Building, Chesterford Research Campus, Little Chesterford, Saffron Walden, Cambs. CB10 1XL, UK.
authors: David M
authors: DM
authors: Wilson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D006801:Humans; D009152:Mutagenicity Tests; D009287:Naphthyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D009287:Naphthyridines; D047428:Protein Kinase Inhibitors
keywords: Azanaphthyridine; Lead optimisation; Medicinal chemistry; Orally bioavailable; Potent; SYK; Selective; Spleen Tyrosine Kinase