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PDBsum entry 5fbo
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Transferase/transferase inhibitor
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PDB id
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5fbo
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References listed in PDB file
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Key reference
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Title
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Discovery of 8-Amino-Imidazo[1,5-A]pyrazines as reversible btk inhibitors for the treatment of rheumatoid arthritis.
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Authors
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J.Liu,
D.Guiadeen,
A.Krikorian,
X.Gao,
J.Wang,
S.B.Boga,
A.B.Alhassan,
Y.Yu,
H.Vaccaro,
S.Liu,
C.Yang,
H.Wu,
A.Cooper,
J.De man,
A.Kaptein,
K.Maloney,
V.Hornak,
Y.D.Gao,
T.O.Fischmann,
H.Raaijmakers,
D.Vu-Pham,
J.Presland,
M.Mansueto,
Z.Xu,
E.Leccese,
J.Zhang-Hoover,
I.Knemeyer,
C.G.Garlisi,
N.Bays,
P.Stivers,
P.E.Brandish,
A.Hicks,
R.Kim,
J.A.Kozlowski.
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Ref.
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Acs Med Chem Lett, 2016,
7,
198-203.
[DOI no: ]
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PubMed id
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Abstract
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Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role
in the B cell receptor (BCR) pathway. It has become an attractive kinase target
for selective B cell inhibition and for the treatment of B cell related
diseases. We report a series of compounds based on
8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with
excellent kinase selectivity. Selectivity is achieved through specific
interactions of the ligand with the kinase hinge and driven by aminopyridine
hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of
trifluoropyridine in the back pocket. These interactions are evident in the
X-ray crystal structure of the lead compounds 1 and 3 in the complex with the
BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the
preclinical rat collagen induced arthritis model.
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