title: Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors.
abstract: A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Frederik J R
authors: FJ
authors: Rombouts
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Gary
authors: G
authors: Tresadern
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Peter
authors: P
authors: Buijnsters
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Xavier
authors: X
authors: Langlois
authors: Villapharma Research S.L., Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo , Km. 2,5- Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
authors: Fulgencio
authors: F
authors: Tovar
authors: Schrödinger GmbH , Dynamostrasse 13, D-68165 Mannheim, Germany.
authors: Thomas B
authors: TB
authors: Steinbrecher
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Greet
authors: G
authors: Vanhoof
authors: Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Marijke
authors: M
authors: Somers
authors: Neuroscience-Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors: José-Ignacio
authors: JI
authors: Andrés
authors: Neuroscience-Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors: Andrés A
authors: AA
authors: Trabanco
keywords: PDE2 inhibitor; Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazine; phosphodiesterase 2 inhibitor; selective; tricycle