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PDBsum entry 5eak
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Transferase/transferase inhibitor
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PDB id
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5eak
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References listed in PDB file
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Key reference
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Title
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Optimization of microtubule affinity regulating kinase (mark) inhibitors with improved physical properties.
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Authors
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D.L.Sloman,
N.Noucti,
M.D.Altman,
D.Chen,
A.C.Mislak,
A.Szewczak,
M.Hayashi,
L.Warren,
T.Dellovade,
Z.Wu,
J.Marcus,
D.Walker,
H.P.Su,
S.C.Edavettal,
S.Munshi,
M.Hutton,
H.Nuthall,
M.G.Stanton.
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Ref.
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Bioorg Med Chem Lett, 2016,
26,
4362-4366.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of microtubule affinity regulating kinase (MARK) represents a
potentially attractive means of arresting neurofibrillary tangle pathology in
Alzheimer's disease. This manuscript outlines efforts to optimize a
pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in
potency, physical properties and attributes amenable to CNS penetration. A
unique cylcyclohexyldiamine scaffold was identified that led to remarkable
improvements in potency, opening up opportunities to reduce MW, Pgp efflux and
improve pharmacokinetic properties while also conferring improved solubility.
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