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PDBsum entry 6cyb
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Hydrolase/hydrolase inhibitor
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PDB id
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6cyb
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References listed in PDB file
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Key reference
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Title
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Structure-Guided design and procognitive assessment of a potent and selective phosphodiesterase 2a inhibitor.
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Authors
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S.J.Stachel,
R.Berger,
A.B.Nomland,
A.T.Ginnetti,
D.V.Paone,
D.Wang,
V.Puri,
H.Lange,
J.Drott,
J.Lu,
J.Marcus,
M.P.Dwyer,
S.Suon,
J.M.Uslaner,
S.M.Smith.
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Ref.
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ACS Med Chem Lett, 2018,
9,
815-820.
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PubMed id
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Abstract
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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.
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