4DDL

PDE10a Crystal Structure Complexed with Novel Inhibitor

4DDL の概要

• エントリーDOI: 10.2210/pdb4ddl/pdb
• 関連するPDBエントリー: 2OUP
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase 10a, hydrolase, 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: 80326.79

構造登録者

Chmait, S.,Jordan, S.,Zhang, J. (登録日: 2012-01-18, 公開日: 2012-03-21, 最終更新日: 2024-11-20)

主引用文献

Hu, E.,Kunz, R.K.,Rumfelt, S.,Chen, N.,Burli, R.,Li, C.,Andrews, K.L.,Zhang, J.,Chmait, S.,Kogan, J.,Lindstrom, M.,Hitchcock, S.A.,Treanor, J.
Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.
Bioorg.Med.Chem.Lett., 22:2262-2265, 2012

PubMed Abstract: We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.

PubMed: 22365755
DOI: 10.1016/j.bmcl.2012.01.086

実験手法

X-RAY DIFFRACTION (2.07 Å)