6KE0

Crystal structure of PDE10A in complex with a triazolopyrimidine inhibitor

Summary for 6KE0

• Entry DOI: 10.2210/pdb6ke0/pdb
• Related: 6KDX 6KDZ
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 79753.69

Authors

Amano, Y.,Honbou, K. (deposition date: 2019-07-03, release date: 2019-08-14, Last modification date: 2023-11-22)

Primary citation

Chino, A.,Honda, S.,Morita, M.,Yonezawa, K.,Hamaguchi, W.,Amano, Y.,Moriguchi, H.,Yamazaki, M.,Aota, M.,Tomishima, M.,Masuda, N.
Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.
Bioorg.Med.Chem., 27:3692-3706, 2019

PubMed Abstract: Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.

PubMed: 31301949
DOI: 10.1016/j.bmc.2019.07.010

Experimental method

X-RAY DIFFRACTION (2.95 Å)