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PDBsum entry 5lmb
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References listed in PDB file
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Key reference
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Title
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Optimisation of a novel series of potent and orally bioavailable azanaphthyridine syk inhibitors.
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Authors
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N.S.Garton,
M.D.Barker,
R.P.Davis,
C.Douault,
E.Hooper-Greenhill,
E.Jones,
H.D.Lewis,
J.Liddle,
D.Lugo,
S.Mccleary,
A.G.S.Preston,
C.Ramirez-Molina,
M.Neu,
T.J.Shipley,
D.O.Somers,
R.J.Watson,
D.M.Wilson.
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Ref.
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Bioorg Med Chem Lett, 2016,
26,
4606-4612.
[DOI no: ]
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PubMed id
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Abstract
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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.
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