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Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

ABSTRACT: Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 ?M. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

SUBMITTER: Buijnsters P

PROVIDER: S-EPMC4160764 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

Buijnsters Peter P De Angelis Meri M Langlois Xavier X Rombouts Frederik J R FJ Sanderson Wendy W Tresadern Gary G Ritchie Alison A Trabanco Andrés A AA VanHoof Greet G Roosbroeck Yves Van YV Andrés José-Ignacio JI

ACS medicinal chemistry letters 20140722 9

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive ...[more]

PMID: 25221665

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