Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Garton, Neil S.; Barker, Michael D.; Davis, Rob P.; Douault, Clement; Hooper-Greenhill, Edward; Jones, Emma; Lewis, Huw D.; Liddle, John; Lugo, Dave; McCleary, Scott; Preston, Alex G.S.; Ramirez-Molina, Cesar; Neu, Margarete; Shipley, Tracy J.; Somers, Don O.; Watson, Robert J.; Wilson, David M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4606
• Page End: 4612
• Publication Date: 2016-10-01
• Subjects: SYK -- Spleen Tyrosine Kinase -- Selective -- Potent -- Orally bioavailable -- Azanaphthyridine -- Lead optimisation -- Medicinal chemistry; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.070
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 p K a . Morpholine compound32 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.