4BBX

Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia

4BBX の概要

• エントリーDOI: 10.2210/pdb4bbx/pdb
• 関連するPDBエントリー: 1LRB 2WEY 2Y0J 4AEL 4AJD 4AJF 4AJG 4AJM
• 分子名称: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A, 4-[3-[1-[(2S)-2-methoxypropyl]pyrazol-4-yl]-2-methyl-imidazo[1,2-a]pyrazin-8-yl]morpholine, ZINC ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase inhibitor, inhibitor complex, hydrolase, zinc binding, magnesium binding
• 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: 78873.80

構造登録者

Bartolome-Nebreda, J.M.,Conde-Ceide, S.,Delgado, F.,Martin, M.L.,Martinez-Viturro, C.M.,Pastor, J.,Tong, H.M.,Iturrino, L.,Macdonald, G.J.,Sanderson, W.,Megens, A.,Langlois, X.,Somers, M.,Vanhoof, G. (登録日: 2012-09-28, 公開日: 2013-10-16, 最終更新日: 2024-05-08)

主引用文献

Bartolome-Nebreda, J.M.,Delgado, F.,Martin, M.L.,Martinez-Viturro, C.M.,Pastor, J.,Tong, H.M.,Iturrino, L.,Macdonald, G.J.,Sanderson, W.E.,Megens, A.,Langlois, X.,Somers, M.,Vanhoof, G.,Conde Ceide, S.
Discovery of a Potent, Selective and Orally Active Pde10A Inhibitor for the Potential Treatment of Schizophrenia.
J.Med.Chem., 57:4196-, 2014

PubMed Abstract: We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

PubMed: 24758746
DOI: 10.1021/JM500073H

実験手法

X-RAY DIFFRACTION (2.5 Å)