 |
PDBsum entry 5axq
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
5axq
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Design and synthesis of a novel 2-Oxindole scaffold as a highly potent and brain-Penetrant phosphodiesterase 10a inhibitor.
|
|
|
Authors
|
|
M.Yoshikawa,
H.Kamisaki,
J.Kunitomo,
H.Oki,
H.Kokubo,
A.Suzuki,
T.Ikemoto,
K.Nakashima,
N.Kamiguchi,
A.Harada,
H.Kimura,
T.Taniguchi.
|
|
|
Ref.
|
|
Bioorg Med Chem Lett, 2015,
23,
7138-7149.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors
based on the 2-oxindole scaffold were designed and synthesized.
(2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein
(P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory
activity (IC50=0.94nM). We performed an optimization study to improve both the
P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based
drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A.
Finally,
1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
(19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A
inhibitory activity (IC50=0.080nM). Compound 19e also exhibited satisfactory
brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum
effective dose of 0.3mg/kg by oral administration in mice.
|
|
|
|
|
|
|
