title: Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.
abstract: The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.
authors.affiliation: Janssen Research & Development, Medicinal Chemistry, Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain. iandres@its.jnj.com
authors.forename: José-Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Peter
authors.initials: P
authors.lastname: Buijnsters
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Frederik
authors.initials: F
authors.lastname: Rombouts
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
mesh_terms: D000818:Animals; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2