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PDBsum entry 4tpm
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Hydrolase/hydrolase inhibitor
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PDB id
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4tpm
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References listed in PDB file
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Key reference
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Title
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Synthesis and preliminary biological evaluation of potent and selective 2-(3-Alkoxy-1-Azetidinyl) quinolines as novel pde10a inhibitors with improved solubility.
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Authors
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R.M.Rzasa,
M.J.Frohn,
K.L.Andrews,
S.Chmait,
N.Chen,
J.G.Clarine,
C.Davis,
H.A.Eastwood,
D.B.Horne,
E.Hu,
A.D.Jones,
M.R.Kaller,
R.K.Kunz,
S.Miller,
H.Monenschein,
T.Nguyen,
A.J.Pickrell,
A.Porter,
A.Reichelt,
X.Zhao,
J.J.Treanor,
J.R.Allen.
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Ref.
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Bioorg Med Chem Lett, 2014,
22,
6570-6585.
[DOI no: ]
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PubMed id
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Abstract
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We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl)
quinolines as potent and selective PDE10A inhibitors. Structure-activity studies
improved the solubility (pH 7.4) and maintained high PDE10A activity compared to
initial lead compound 3, with select compounds demonstrating good oral
bioavailability. X-ray crystallographic studies revealed two distinct binding
modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy
assay in rats demonstrated that this series of compounds covered the target
within the striatum.
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