PDBsum entry 4yqh

Hydrolase/hydrolase inhibitor

PDB id: 4yqh

Contents

Protein chains

321 a.a.

Ligands

4F7 ×2

Metals

_ZN ×2

_MG ×2

Waters ×48

PDB id:

4yqh

Name:

Hydrolase/hydrolase inhibitor

Title:

2-[2-(4-phenyl-1h-imidazol-2-yl)ethyl]quinoxaline (sunovion compound 14) co-crystallized with pde10a

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: unp residues 449-769. Synonym: pde10a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.31Å R-factor: 0.240 R-free: 0.301

Authors:

D.Burdi,L.Herman,T.Wang

Key ref:

D.F.Burdi et al. (2015). Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A. Bioorg Med Chem Lett, 25, 1864-1868. PubMed id: 25863433 DOI: 10.1016/j.bmcl.2015.03.050

Date:

13-Mar-15 Release date: 29-Apr-15

Protein chains

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

Seq: 1055 a.a.

Struc: 321 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.bmcl.2015.03.050

Bioorg Med Chem Lett 25:1864-1868 (2015)

PubMed id: 25863433

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

D.F.Burdi, J.E.Campbell, J.Wang, S.Zhao, H.Zhong, J.Wei, U.Campbell, L.Shao, L.Herman, P.Koch, P.G.Jones, M.C.Hewitt.

ABSTRACT

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1mg/kg.