PDBsum entry 4p0n

Hydrolase/hydrolase inhibitor

PDB id: 4p0n

Contents

Protein chains

307 a.a.

Ligands

1IS-1IR

SO4 ×6

GOL ×2

1IR-1IS

Metals

_ZN ×4

Waters ×553

PDB id:

4p0n

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pde10a with a novel imidazo[4,5-b]pyridine inhibitor

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:

2.08Å R-factor: 0.160 R-free: 0.182

Authors:

S.Chmait

Key ref:

E.Hu et al. (2014). Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A). Acs Med Chem Lett, 5, 700-705. PubMed id: 24944747 DOI: 10.1021/ml5000993

Date:

21-Feb-14 Release date: 01-Oct-14

Protein chains

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

Seq: 1055 a.a.

Struc: 307 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: 10.1021/ml5000993

Acs Med Chem Lett 5:700-705 (2014)

PubMed id: 24944747

Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).

E.Hu, K.Andrews, S.Chmait, X.Zhao, C.Davis, S.Miller, G.Hill Della Puppa, M.Dovlatyan, H.Chen, D.Lester-Zeiner, J.Able, C.Biorn, J.Ma, J.Shi, J.Treanor, J.R.Allen.

ABSTRACT

We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure-activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.