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PDBsum entry 4nwm
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Transferase/transferase inhibitor
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PDB id
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4nwm
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References listed in PDB file
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Key reference
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Title
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Purine derivatives as potent bruton'S tyrosine kinase (btk) inhibitors for autoimmune diseases.
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Authors
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Q.Shi,
A.Tebben,
A.J.Dyckman,
H.Li,
C.Liu,
J.Lin,
S.Spergel,
J.R.Burke,
K.W.Mcintyre,
G.C.Olini,
J.Strnad,
N.Surti,
J.K.Muckelbauer,
C.Chang,
Y.An,
L.Cheng,
Q.Ruan,
K.Leftheris,
P.H.Carter,
J.Tino,
G.V.De lucca.
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Ref.
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Bioorg Med Chem Lett, 2014,
24,
2206-2211.
[DOI no: ]
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PubMed id
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Abstract
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Investigation of various heterocyclic core isosteres of imidazopyrazines 1 &
2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors.
Subsequent SAR studies of the purine series led to the discovery of 20 as a
leading compound. Compound 20 is very selective when screened against a panel of
400 kinases and is a potent inhibitor in cellular assays of human B cell
function including B-Cell proliferation and CD86 cell surface expression and
exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure
with BTK shows that the high selectivity is gained from filling a BTK specific
lipophilic pocket. However, physical and ADME properties leading to low oral
exposure hindered further development.
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