PDBsum entry 5axq

Hydrolase/hydrolase inhibitor

PDB id: 5axq

Contents

Protein chains

315 a.a.

Ligands

4LP

4LK

Metals

_MG ×2

_ZN ×2

Waters ×401

PDB id:

5axq

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the catalytic domain of pde10a complexed with highly potent and brain-penetrant pde10a inhibitor with 2-oxindole scaffold

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain, residues 442-779. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.77Å R-factor: 0.173 R-free: 0.211

Authors:

H.Oki,Y.Zama

Key ref:

M.Yoshikawa et al. (2015). Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor. Bioorg Med Chem Lett, 23, 7138-7149. PubMed id: 26494583 DOI: 10.1016/j.bmc.2015.10.002

Date:

31-Jul-15 Release date: 11-Nov-15

Protein chains

Q9Y233  (PDE10_HUMAN) -  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A from Homo sapiens

Seq: 1055 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.17 - 3',5'-cyclic-nucleotide phosphodiesterase.
• Reaction: a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmc.2015.10.002

Bioorg Med Chem Lett 23:7138-7149 (2015)

PubMed id: 26494583

Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.

M.Yoshikawa, H.Kamisaki, J.Kunitomo, H.Oki, H.Kokubo, A.Suzuki, T.Ikemoto, K.Nakashima, N.Kamiguchi, A.Harada, H.Kimura, T.Taniguchi.

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.