5B25

Crystal structure of human PDE1B with inhibitor 3

5B25 の概要

• エントリーDOI: 10.2210/pdb5b25/pdb
• 分子名称: Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: hydrolase, 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: Q01064
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 158383.14

構造登録者

Ida, K.,Lane, W.,Snell, G.,Sogabe, S. (登録日: 2016-01-07, 公開日: 2016-02-03, 最終更新日: 2023-11-08)

主引用文献

Li, P.,Zheng, H.,Zhao, J.,Zhang, L.,Yao, W.,Zhu, H.,Beard, J.D.,Ida, K.,Lane, W.,Snell, G.,Sogabe, S.,Heyser, C.J.,Snyder, G.L.,Hendrick, J.P.,Vanover, K.E.,Davis, R.E.,Wennogle, L.P.
Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases
J.Med.Chem., 59:1149-1164, 2016

PubMed Abstract: A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

PubMed: 26789933
DOI: 10.1021/acs.jmedchem.5b01751

実験手法

X-RAY DIFFRACTION (1.9 Å)