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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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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of the catalytic domain of pde10a complexed with 5- methoxy-3-(1-phenyl-1h-pyrazol-5-yl)-1-(3-(trifluoromethyl)phenyl) pyridazin-4(1h)-one
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Structure:
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Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain, unp residues 442-779. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.68Å
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R-factor:
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0.203
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R-free:
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0.261
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Authors:
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H.Oki,Y.Hayano
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Key ref:
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J.Kunitomo
et al.
(2014).
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.
J Med Chem,
57,
9627-9643.
PubMed id:
DOI:
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Date:
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01-Sep-14
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Release date:
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19-Nov-14
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PROCHECK
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Headers
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References
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Q9Y233
(PDE10_HUMAN) -
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A from Homo sapiens
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Seq:
Struc:
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1055 a.a.
315 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.1.4.17
- 3',5'-cyclic-nucleotide phosphodiesterase.
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Reaction:
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a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H+
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nucleoside 3',5'-cyclic phosphate
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+
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H2O
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=
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nucleoside 5'-phosphate
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
57:9627-9643
(2014)
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PubMed id:
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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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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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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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