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ID: ALA4431389

Journal: Bioorg Med Chem Lett

Title: Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.

Authors: Garton NS, Barker MD, Davis RP, Douault C, Hooper-Greenhill E, Jones E, Lewis HD, Liddle J, Lugo D, McCleary S, Preston AGS, Ramirez-Molina C, Neu M, Shipley TJ, Somers DO, Watson RJ, Wilson DM.

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.

CiteXplore: 27578246

DOI: 10.1016/j.bmcl.2016.08.070