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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Aug 22

PMID 30128073

Citations 3

Authors

Shawn J Stachel

Richard Berger

Ashley B Nomland

Anthony T Ginnetti

Daniel V Paone

Deping Wang

Vanita Puri

Henry Lange

Jason Drott

Jun Lu

Jacob Marcus

Michael P Dwyer

Sokreine Suon

Jason M Uslaner

Sean M Smith

Affiliations

Soon will be listed here.

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.

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