4YQH

2-[2-(4-Phenyl-1H-imidazol-2-yl)ethyl]quinoxaline (Sunovion Compound 14) co-crystallized with PDE10A

4YQH の概要

• エントリーDOI: 10.2210/pdb4yqh/pdb
• 関連するPDBエントリー: 4YS7
• 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, pde10a, co-crystal, 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: 75101.77

構造登録者

Burdi, D.,Herman, L.,Wang, T. (登録日: 2015-03-13, 公開日: 2015-04-29, 最終更新日: 2024-02-28)

主引用文献

Burdi, D.F.,Campbell, J.E.,Wang, J.,Zhao, S.,Zhong, H.,Wei, J.,Campbell, U.,Shao, L.,Herman, L.,Koch, P.,Jones, P.G.,Hewitt, M.C.
Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.
Bioorg.Med.Chem.Lett., 25:1864-1868, 2015

PubMed Abstract: The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

PubMed: 25863433
DOI: 10.1016/j.bmcl.2015.03.050

実験手法

X-RAY DIFFRACTION (2.308 Å)