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

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• 作者：Peter Buijnsters ; Meri De Angelis ; Xavier Langlois ; Frederik J. R. Rombouts ; Wendy Sanderson ; Gary Tresadern ; Alison Ritchie ; Andr茅s A. Trabanco ; Greet VanHoof ; Yves Van Roosbroeck ; Jos茅-Ignacio Andr茅s
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：5
• 期：9
• 页码：1049-1053
• 全文大小：372K
• ISSN：1948-5875

文摘

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 渭M. 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.

Keywords:

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