6CYB

PDE2 in complex with compound 7

Summary for 6CYB

• Entry DOI: 10.2210/pdb6cyb/pdb
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: pde2, inhibition, structure-guided design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 88878.13

Authors

Lu, J. (deposition date: 2018-04-05, release date: 2018-09-19, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.62 Å)