PDBsum entry 4tpm

Hydrolase/hydrolase inhibitor

PDB id: 4tpm

Contents

Protein chains

303 a.a.

Ligands

SO4 ×14

GOL

35E ×2

Metals

_ZN ×4

Waters ×63

PDB id:

4tpm

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as pde10a inhibitors

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: unp residues 452-789. Engineered: yes

Source:

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

Resolution:

2.77Å R-factor: 0.152 R-free: 0.179

Authors:

S.Chmait

Key ref:

R.M.Rzasa et al. (2014). Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility. Bioorg Med Chem Lett, 22, 6570-6585. PubMed id: 25456383 DOI: 10.1016/j.bmc.2014.10.013

Date:

08-Jun-14 Release date: 17-Dec-14

Protein chains

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

Seq: 1055 a.a.

Struc: 303 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⁺

nucleoside 3',5'-cyclic phosphate (Bound ligand (Het Group name = GOL) matches with 46.15% similarity) + H2O = nucleoside 5'-phosphate + H(+)

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

Added reference

DOI no: 10.1016/j.bmc.2014.10.013

Bioorg Med Chem Lett 22:6570-6585 (2014)

PubMed id: 25456383

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.

R.M.Rzasa, M.J.Frohn, K.L.Andrews, S.Chmait, N.Chen, J.G.Clarine, C.Davis, H.A.Eastwood, D.B.Horne, E.Hu, A.D.Jones, M.R.Kaller, R.K.Kunz, S.Miller, H.Monenschein, T.Nguyen, A.J.Pickrell, A.Porter, A.Reichelt, X.Zhao, J.J.Treanor, J.R.Allen.

ABSTRACT

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.