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PDBsum entry 4e90
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Hydrolase/hydrolase inhibitor
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PDB id
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4e90
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References listed in PDB file
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Key reference
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Title
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Application of structure-Based drug design and parallel chemistry to identify selective, Brain penetrant, In vivo active phosphodiesterase 9a inhibitors.
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Authors
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M.M.Claffey,
C.J.Helal,
P.R.Verhoest,
Z.Kang,
K.S.Fors,
S.Jung,
J.Zhong,
M.W.Bundesmann,
X.Hou,
S.Lui,
R.J.Kleiman,
M.Vanase-Frawley,
A.W.Schmidt,
F.Menniti,
C.J.Schmidt,
W.E.Hoffman,
M.Hajos,
L.Mcdowell,
R.E.O'Connor,
M.Macdougall-Murphy,
K.R.Fonseca,
S.L.Becker,
F.R.Nelson,
S.Liras.
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Ref.
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J Med Chem, 2012,
55,
9055-9068.
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PubMed id
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Abstract
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Phosphodiesterase 9A inhibitors have shown activity in preclinical models of
cognition with potential application as novel therapies for treating Alzheimer's
disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS
permeability in rats with modest asymmetry between central and peripheral
compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had
physicochemical properties outside the range associated with traditional CNS
drugs. To address the potential risk of restricted CNS penetration with 2 in
human clinical trials, we sought to identify a preclinical candidate with no
asymmetry in rat brain penetration and that could advance into development.
Merging the medicinal chemistry strategies of structure-based design with
parallel chemistry, a novel series of PDE9A inhibitors was identified that
showed improved selectivity over PDE1C. Optimization afforded preclinical
candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced
microsomal clearance along with the ability to increase cyclic guanosine
monophosphosphate levels in rat CSF.
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