Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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=0.94 nM). 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=0.080 nM). 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.
...
PMID:Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor. 2649 83
