6CYC

PDE2 in complex with compound 5

6CYC の概要

• エントリーDOI: 10.2210/pdb6cyc/pdb
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: pde2, inhibition, structure-guided design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88960.34

構造登録者

Lu, J. (登録日: 2018-04-05, 公開日: 2018-09-19, 最終更新日: 2024-03-06)

主引用文献

Stachel, S.J.,Berger, R.,Nomland, A.B.,Ginnetti, A.T.,Paone, D.V.,Wang, D.,Puri, V.,Lange, H.,Drott, J.,Lu, J.,Marcus, J.,Dwyer, M.P.,Suon, S.,Uslaner, J.M.,Smith, S.M.
Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.
ACS Med Chem Lett, 9:815-820, 2018

PubMed Abstract: Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound , while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, , demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

PubMed: 30128073
DOI: 10.1021/acsmedchemlett.8b00214

実験手法

X-RAY DIFFRACTION (1.54 Å)