5TZC

Crystal Structure of human PDE2a in complex with (5S)-1-[(3-bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

5TZC の概要

• エントリーDOI: 10.2210/pdb5tzc/pdb
• 関連するPDBエントリー: 5TZ3 5TZA 5TZH 5TZW 5TZX 5TZZ 5U00
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, (3-bromo-4-fluorophenyl)[(5S)-3,3-difluoro-5-(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]methanone, ZINC ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 162848.04

構造登録者

Xu, R.,Aertgeerts, K. (登録日: 2016-11-21, 公開日: 2017-02-22, 最終更新日: 2024-03-06)

主引用文献

Gomez, L.,Massari, M.E.,Vickers, T.,Freestone, G.,Vernier, W.,Ly, K.,Xu, R.,McCarrick, M.,Marrone, T.,Metz, M.,Yan, Y.G.,Yoder, Z.W.,Lemus, R.,Broadbent, N.J.,Barido, R.,Warren, N.,Schmelzer, K.,Neul, D.,Lee, D.,Andersen, C.B.,Sebring, K.,Aertgeerts, K.,Zhou, X.,Tabatabaei, A.,Peters, M.,Breitenbucher, J.G.
Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.
J. Med. Chem., 60:2037-2051, 2017

PubMed Abstract: A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.

PubMed: 28165743
DOI: 10.1021/acs.jmedchem.6b01793

実験手法

X-RAY DIFFRACTION (2.36 Å)