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PDBsum entry 3wyl
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Hydrolase/hydrolase inhibitor
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PDB id
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3wyl
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References listed in PDB file
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Key reference
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Title
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Discovery of 1-[2-Fluoro-4-(1h-Pyrazol-1-Yl)phenyl]-5-Methoxy-3-(1-Phenyl-1h-Pyrazol-5-Yl)pyridazin-4(1h)-One (tak-063), A highly potent, Selective, And orally active phosphodiesterase 10a (pde10a) inhibitor.
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Authors
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J.Kunitomo,
M.Yoshikawa,
M.Fushimi,
A.Kawada,
J.F.Quinn,
H.Oki,
H.Kokubo,
M.Kondo,
K.Nakashima,
N.Kamiguchi,
K.Suzuki,
H.Kimura,
T.Taniguchi.
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Ref.
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J Med Chem, 2014,
57,
9627-9643.
[DOI no: ]
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PubMed id
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Abstract
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A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors
were synthesized. Our optimization efforts using structure-based drug design
(SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in
complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs)
led to the identification of
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
(27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent
selectivity (>15000-fold selectivity over other PDEs), and favorable
pharmacokinetics, including high brain penetration, in mice. Oral administration
of compound 27h to mice elevated striatal 3',5'-cyclic adenosine monophosphate
(cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and
showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a
minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently
being evaluated in clinical trials for the treatment of schizophrenia.
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