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

[Display omitted] 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 a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-10, Vol.26 (19), p.4606-4612
Main 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.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Azanaphthyridine
Biological Availability
Crystallography, X-Ray
Humans
Lead optimisation
Medicinal chemistry
Mutagenicity Tests
Naphthyridines - administration & dosage
Naphthyridines - pharmacokinetics
Naphthyridines - pharmacology
Orally bioavailable
Potent
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Rats
Selective
Spleen Tyrosine Kinase
Structure-Activity Relationship
SYK
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Description
Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.08.070