Literature DB >> 25221665

Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

Peter Buijnsters1, Meri De Angelis2, Xavier Langlois1, Frederik J R Rombouts1, Wendy Sanderson3, Gary Tresadern3, Alison Ritchie4, Andrés A Trabanco2, Greet VanHoof3, Yves Van Roosbroeck1, José-Ignacio Andrés2.   

Abstract

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

Entities:  

Keywords:  PDE2 inhibitor; [1,2,4]triazolo[4,3-a]quinoxalines; phosphodiesterase 2; target engagement

Year:  2014        PMID： 25221665      PMCID： PMC4160764          DOI： 10.1021/ml500262u

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  17 in total

Review 1.  Advances in targeting cyclic nucleotide phosphodiesterases.

Authors:  Donald H Maurice; Hengming Ke; Faiyaz Ahmad; Yousheng Wang; Jay Chung; Vincent C Manganiello
Journal:  Nat Rev Drug Discov       Date:  2014-04       Impact factor: 84.694

2.  Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors.

Authors:  Kris Rutten; Jos Prickaerts; Martin Hendrix; F Josef van der Staay; Ayhan Sik; Arjan Blokland
Journal:  Eur J Pharmacol       Date:  2006-12-01       Impact factor: 4.432

3.  The specific role of cGMP in hippocampal LTP.

Authors:  H Son; Y F Lu; M Zhuo; O Arancio; E R Kandel; R D Hawkins
Journal:  Learn Mem       Date:  1998 Jul-Aug       Impact factor: 2.460

4.  Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.

Authors:  José-Ignacio Andrés; Peter Buijnsters; Meri De Angelis; Xavier Langlois; Frederik Rombouts; Andrés A Trabanco; Greet Vanhoof
Journal:  Bioorg Med Chem Lett       Date:  2012-12-01       Impact factor: 2.823

5.  Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system.

Authors:  André Iffland; Darcy Kohls; Simon Low; Jing Luan; Yan Zhang; Michael Kothe; Qing Cao; Ajith V Kamath; Yuan-Hua Ding; Tom Ellenberger
Journal:  Biochemistry       Date:  2005-06-14       Impact factor: 3.162

6.  Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues.

Authors:  Viktor Lakics; Eric H Karran; Frank G Boess
Journal:  Neuropharmacology       Date:  2010-05-21       Impact factor: 5.250

7.  cGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation.

Authors:  Jos Prickaerts; Jan de Vente; Wiel Honig; Harry W M Steinbusch; Arjan Blokland
Journal:  Eur J Pharmacol       Date:  2002-02-01       Impact factor: 4.432

8.  Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons.

Authors:  U Frey; Y Y Huang; E R Kandel
Journal:  Science       Date:  1993-06-11       Impact factor: 47.728

9.  Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct.

Authors:  Jayvardhan Pandit; Michael D Forman; Kimberly F Fennell; Keith S Dillman; Frank S Menniti
Journal:  Proc Natl Acad Sci U S A       Date:  2009-10-14       Impact factor: 11.205

10.  Hydrolysis of N-methyl-D-aspartate receptor-stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus.

Authors:  Neesha U Suvarna; James M O'Donnell
Journal:  J Pharmacol Exp Ther       Date:  2002-07       Impact factor: 4.030
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  7 in total

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

Authors:  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
Journal:  ACS Med Chem Lett       Date:  2015-01-15       Impact factor: 4.345

2.  Structure of Ddi2, a highly inducible detoxifying metalloenzyme from Saccharomyces cerevisiae.

Authors:  Jia Li; Yunhua Jia; Aiyang Lin; Michelle Hanna; Linda Chelico; Wei Xiao; Stanley A Moore
Journal:  J Biol Chem       Date:  2019-05-31       Impact factor: 5.157

3.  An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains.

Authors:  Filip Fratev; Suman Sirimulla
Journal:  Sci Rep       Date:  2019-11-14       Impact factor: 4.379

4.  Long-Timescale Simulations Revealed Critical Non-Conserved Residues of Phosphodiesterases Affecting Selectivity of BAY60-7550.

Authors:  Qing Liu; Menghua Song; Yue Qiu; Elaine Lai-Han Leung; Qiang Huang; Xiaojun Yao
Journal:  Comput Struct Biotechnol J       Date:  2022-09-13       Impact factor: 6.155

5.  Chemical Space Exploration with Active Learning and Alchemical Free Energies.

Authors:  Yuriy Khalak; Gary Tresadern; David F Hahn; Bert L de Groot; Vytautas Gapsys
Journal:  J Chem Theory Comput       Date:  2022-09-23       Impact factor: 6.578

6.  Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation.

Authors:  Laura Pérez-Benito; Henrik Keränen; Herman van Vlijmen; Gary Tresadern
Journal:  Sci Rep       Date:  2018-03-20       Impact factor: 4.379

7.  DeltaDelta neural networks for lead optimization of small molecule potency.

Authors:  José Jiménez-Luna; Laura Pérez-Benito; Gerard Martínez-Rosell; Simone Sciabola; Rubben Torella; Gary Tresadern; Gianni De Fabritiis
Journal:  Chem Sci       Date:  2019-10-16       Impact factor: 9.825
  7 in total

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