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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

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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 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 ...[more]

PMID: 30128073

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