4WN1

Crystal structure of PDE10A in complex with 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one

4WN1 の概要

• エントリーDOI: 10.2210/pdb4wn1/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: phosphodiesterase, complex, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9Y233
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79814.77

構造登録者

Amano, Y.,Honbou, K. (登録日: 2014-10-10, 公開日: 2014-12-31, 最終更新日: 2023-12-27)

主引用文献

Hamaguchi, W.,Masuda, N.,Miyamoto, S.,Shiina, Y.,Kikuchi, S.,Mihara, T.,Moriguchi, H.,Fushiki, H.,Murakami, Y.,Amano, Y.,Honbou, K.,Hattori, K.
Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition.
Bioorg.Med.Chem., 23:297-313, 2015

PubMed Abstract: A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.

PubMed: 25515954
DOI: 10.1016/j.bmc.2014.11.039

実験手法

X-RAY DIFFRACTION (3.13 Å)