4TPM

Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as PDE10A Inhibitors

4TPM の概要

• エントリーDOI: 10.2210/pdb4tpm/pdb
• 関連するPDBエントリー: 4TPP
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, SULFATE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: pde10a, quinolines, 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: 83632.34

構造登録者

Chmait, S. (登録日: 2014-06-08, 公開日: 2014-12-17, 最終更新日: 2024-11-13)

主引用文献

Rzasa, R.M.,Frohn, M.J.,Andrews, K.L.,Chmait, S.,Chen, N.,Clarine, J.G.,Davis, C.,Eastwood, H.A.,Horne, D.B.,Hu, E.,Jones, A.D.,Kaller, M.R.,Kunz, R.K.,Miller, S.,Monenschein, H.,Nguyen, T.,Pickrell, A.J.,Porter, A.,Reichelt, A.,Zhao, X.,Treanor, J.J.,Allen, J.R.
Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.
Bioorg.Med.Chem., 22:6570-6585, 2014

PubMed Abstract: We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

PubMed: 25456383
DOI: 10.1016/j.bmc.2014.10.013

実験手法

X-RAY DIFFRACTION (2.77 Å)