Unknown

Dataset Information

0

Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.

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 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 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, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

SUBMITTER: Stachel SJ 

PROVIDER: S-EPMC6088355 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.

Stachel Shawn J SJ   Berger Richard R   Nomland Ashley B AB   Ginnetti Anthony T AT   Paone Daniel V DV   Wang Deping D   Puri Vanita V   Lange Henry H   Drott Jason J   Lu Jun J   Marcus Jacob J   Dwyer Michael P MP   Suon Sokreine S   Uslaner Jason M JM   Smith Sean M SM  

ACS medicinal chemistry letters 20180726 8

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 <b>3</b>, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound <b>3</b> was subsequently optimized for improved PDE2 activity and isoform selectivity  ...[more]

Similar Datasets

Transcriptomics Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
2023-12-31 | GSE235595 | GEO
Unknown Structure-Guided Design of Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors.
| S-EPMC5304296 | biostudies-literature
Unknown Structure-guided design of an Hsp90? N-terminal isoform-selective inhibitor.
| S-EPMC5789826 | biostudies-literature
Unknown Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1.
| S-EPMC4494889 | biostudies-literature
Unknown Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design.
| S-EPMC3469756 | biostudies-literature
Unknown Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7.
| S-EPMC5749250 | biostudies-literature
Unknown Structure-guided design of a potent peptide inhibitor targeting the interaction between CRK and ABL kinase.
| S-EPMC6072116 | biostudies-literature
Unknown Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.
| S-EPMC4755933 | biostudies-literature
Unknown Structure-Based Design of Potent and Selective CK1? Inhibitors.
| S-EPMC4025826 | biostudies-other
Unknown Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.
| S-EPMC4160764 | biostudies-literature