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PDBsum entry 5c28
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Hydrolase/hydrolase inhibitor
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PDB id
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5c28
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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 and optimization of a series of pyrimidine-Based phosphodiesterase 10a (pde10a) inhibitors through fragment screening, Structure-Based design, And parallel synthesis.
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Authors
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W.D.Shipe,
S.S.Sharik,
J.C.Barrow,
G.B.Mcgaughey,
C.R.Theberge,
J.M.Uslaner,
Y.Yan,
J.J.Renger,
S.M.Smith,
P.J.Coleman,
C.D.Cox.
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Ref.
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J Med Chem, 2015,
58,
7888-7894.
[DOI no: ]
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PubMed id
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Abstract
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Screening of a fragment library for PDE10A inhibitors identified a low molecular
weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial
optimization by catalog followed by iterative parallel synthesis guided by X-ray
cocrystal structures resulted in rapid potency improvements with minimal loss of
ligand efficiency. Compound 15h, with PDE10A Ki of 8.2 pM, LE of 0.49, and
>5000-fold selectivity over other PDEs, fully attenuates MK-801-induced
hyperlocomotor activity after ip dosing.
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