title: 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 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 impairment and other central nervous system related disorders.
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Buijnsters
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Frederik J R
authors.initials: FJ
authors.lastname: Rombouts
authors.affiliation: Discovery Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sanderson
authors.affiliation: Discovery Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: BioFocus , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
authors.forename: Alison
authors.initials: A
authors.lastname: Ritchie
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: Discovery Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: VanHoof
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, a Division of Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Yves Van
authors.initials: YV
authors.lastname: Roosbroeck
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors.forename: José-Ignacio
authors.initials: JI
authors.lastname: Andrés
keywords: PDE2 inhibitor; [1,2,4]triazolo[4,3-a]quinoxalines; phosphodiesterase 2; target engagement