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

被引：22

作者：

Andres, Jose-Ignacio ^{[1
]}

Buijnsters, Peter ^{[2
]}

De Angelis, Meri ^{[1
]}

Langlois, Xavier ^{[3
]}

Rombouts, Frederik ^{[2
]}

Trabanco, Andres A. ^{[1
]}

Vanhoof, Greet ^{[4
]}

机构：

[1] Janssen Cilag SA, Janssen Res & Dev, Toledo 45007, Spain

[2] Janssen Pharmaceut NV, Janssen Res & Dev, Neurosci Med Chem, B-2340 Beerse, Belgium

[3] Janssen Pharmaceut NV, Janssen Res & Dev, Neurosci Biol, B-2340 Beerse, Belgium

[4] Janssen Pharmaceut NV, Janssen Res & Dev, CREATe, Translat Sci, B-2340 Beerse, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 03期

关键词：

Neurological disorders; PDE2; inhibitors; PDE10; Triazoloquinoxalines; CGMP; PDE10A; CAMP; RAT; STRIATUM; MEMORY; BRAIN;

D O I：

10.1016/j.bmcl.2012.11.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-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. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：785 / 790

页数：6

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