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PDBsum entry 4rx5
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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 highly potent and selective bruton'S tyrosine kinase inhibitors: pyridazinone analogs with improved metabolic stability.
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Authors
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W.B.Young,
J.Barbosa,
P.Blomgren,
M.C.Bremer,
J.J.Crawford,
D.Dambach,
C.Eigenbrot,
S.Gallion,
A.R.Johnson,
J.E.Kropf,
S.H.Lee,
L.Liu,
J.W.Lubach,
J.Macaluso,
P.Maciejewski,
S.A.Mitchell,
D.F.Ortwine,
J.Di paolo,
K.Reif,
H.Scheerens,
A.Schmitt,
X.Wang,
H.Wong,
J.M.Xiong,
J.Xu,
C.Yu,
Z.Zhao,
K.S.Currie.
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Ref.
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Bioorg Med Chem Lett, 2016,
26,
575-579.
[DOI no: ]
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PubMed id
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Abstract
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BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies,
resulting in a suspension of clinical trials. The primary route of metabolism
was through cleavage of the acyclic amide bond connecting the terminal
tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were
focused on reducing metabolic cleavage of this amide, and resulted in the
identification of several central aryl linker substituents that conferred
improved stability. The most promising substituted aryl linkers were then
incorporated into an optimized pyridazinone scaffold, resulting in the
identification of lead analog 23, possessing improved potency, metabolic
stability and preclinical properties.
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