6KDX

Crystal structure of PDE10A in complex with a triazolopyrimidine inhibitor

6KDX の概要

• エントリーDOI: 10.2210/pdb6kdx/pdb
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79710.66

構造登録者

Amano, Y.,Honbou, K. (登録日: 2019-07-03, 公開日: 2019-08-14, 最終更新日: 2023-11-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.44 Å)