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PDBsum entry 5b4k
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Hydrolase/hydrolase inhibitor
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PDB id
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5b4k
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References listed in PDB file
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Key reference
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Title
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Design and synthesis of potent and selective pyridazin-4(1h)-One-Based pde10a inhibitors interacting with tyr683 in the pde10a selectivity pocket.
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Authors
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M.Yoshikawa,
T.Hitaka,
T.Hasui,
M.Fushimi,
J.Kunitomo,
H.Kokubo,
H.Oki,
K.Nakashima,
T.Taniguchi.
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Ref.
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Bioorg Med Chem Lett, 2016,
24,
3447-3455.
[DOI no: ]
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PubMed id
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Abstract
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Utilizing structure-based drug design techniques, we designed and synthesized
phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These
compounds can interact with Tyr683 in the PDE10A selectivity pocket.
Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through
an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A
selectivity pocket. After optimizing the linker length, we identified
1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
(16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and
perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The
crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety
was located deep within the PDE10A selectivity pocket and interacted with
Tyr683. Additionally, a bidentate interaction existed between the
5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.
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