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PDBsum entry 3w5e
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Hydrolase/hydrolase inhibitor
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PDB id
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3w5e
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References listed in PDB file
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Key reference
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Title
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Identification of the fused bicyclic 4-Amino-2-Phenylpyrimidine derivatives as novel and potent pde4 inhibitors.
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Authors
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T.Goto,
A.Shiina,
T.Yoshino,
K.Mizukami,
K.Hirahara,
O.Suzuki,
Y.Sogawa,
T.Takahashi,
T.Mikkaichi,
N.Nakao,
M.Takahashi,
M.Hasegawa,
S.Sasaki.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
3325-3328.
[DOI no: ]
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PubMed id
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Abstract
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2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was
found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150nM). A
number of derivatives with a variety of 4-amino substituents and fused bicyclic
pyrimidines were synthesized. Among these,
5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed
potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide
derivative (31b) was determined as a potent inhibitor for both PDE4B
(IC50=7.5nM) and TNF-α production in mouse splenocytes (IC50=9.8nM) and showed
good in vivo anti-inflammatory activity in the LPS-induced lung inflammation
model in mice (ID50=18mg/kg). The binding mode of the new inhibitor (31e) in the
catalytic site of PDE4B is presented based on an X-ray crystal structure of the
ligand-enzyme complex.
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