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Pyrido[4,3‑e][1,2,4]triazolo[4,3‑a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

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journal contribution
posted on 12.03.2015, 00:00 by Frederik J. R. Rombouts, Gary Tresadern, Peter Buijnsters, Xavier Langlois, Fulgencio Tovar, Thomas B. Steinbrecher, Greet Vanhoof, Marijke Somers, José-Ignacio Andrés, Andrés A. Trabanco
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.