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PDBsum entry 4y86
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Hydrolase/hydrolase inhibitor
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PDB id
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4y86
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References listed in PDB file
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Key reference
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Title
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Structural asymmetry of phosphodiesterase-9a and a unique pocket for selective binding of a potent enantiomeric inhibitor.
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Authors
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M.Huang,
Y.Shao,
J.Hou,
W.Cui,
B.Liang,
Y.Huang,
Z.Li,
Y.Wu,
X.Zhu,
P.Liu,
Y.Wan,
H.Ke,
H.B.Luo.
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Ref.
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Mol Pharmacol, 2015,
88,
836-845.
[DOI no: ]
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PubMed id
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Abstract
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Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential
therapeutics for treatment of central nervous system diseases and diabetes.
Here, we report the discovery of a new category of PDE9 inhibitors by rational
design on the basis of the crystal structures. The best compound,
(S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one
[(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has
bioavailability of 56.5% in the rat pharmacokinetic model. The crystal
structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal
subtle conformational asymmetry of two M-loops in the PDE9 dimer and different
conformations of two C33 enantiomers. The structures also identified a small
hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with
(R)-C33, and is thus possibly useful for improvement of selectivity of PDE9
inhibitors. The asymmetry of the M-loop and the different interactions of the
C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the
design of inhibitors.
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