4MUW: Crystal Structure Of Pde10a With Novel Keto-benzimidazole Inhibitor

Citation:
Abstract
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
PDB ID: 4MUWDownload
MMDB ID: 114561
PDB Deposition Date: 2013/9/23
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 2.64  Å
Source Organism:
Similar Structures:
Biological Unit for 4MUW: dimeric; determined by author
Molecular Components in 4MUW
Label Count Molecule
Proteins (2 molecules)
2
Camp and Camp-inhibited Cgmp 3',5'-cyclic Phosphodiesterase 10A(Gene symbol: PDE10A)
Molecule annotation
Chemicals (22 molecules)
1
4
2
15
3
1
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.