Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors |
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| Authors: | José-Ignacio Andrés Peter Buijnsters Meri De Angelis Xavier Langlois Frederik Rombouts Andrés A Trabanco Greet Vanhoof |
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| Institution: | 1. Janssen Research & Development, Medicinal Chemistry, Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain;2. Janssen Research & Development, Neuroscience-Medicinal Chemistry, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium;3. Janssen Research & Development, Neuroscience-Biology, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium;4. Janssen Research & Development, CREATe, Translational Sciences, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium |
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| Abstract: | The synthesis, preliminary evaluation and structure–activity relationship (SAR) of a series of 1-aryl-4-methyl1,2,4]triazolo4,3-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. |
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