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

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

  • ACS Med Chem Lett. 2015 Jan 15;6(3):282-6. doi: 10.1021/ml500463t.
Frederik J R Rombouts 1,  Gary Tresadern 1,  Peter Buijnsters 1,  Xavier Langlois 1,  Fulgencio Tovar 2,  Thomas B Steinbrecher 3,  Greet Vanhoof 1,  Marijke Somers 1,  José-Ignacio Andrés 4,  Andrés A Trabanco 4
Affiliations

Affiliations

  • 1 Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 2 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.
  • 3 Schrödinger GmbH , Dynamostrasse 13, D-68165 Mannheim, Germany.
  • 4 Neuroscience-Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
PMID: 25815146 DOI: 10.1021/ml500463t
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.

Keywords

PDE2 inhibitor; Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazine; phosphodiesterase 2 inhibitor; selective; tricycle.

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