Novel diamino derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A(2a) receptor antagonists

Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A(2a) receptor antagonists with oral activity in rodent models of Parkinson's disease. We have replaced the piperazinyl group with a variety of linear, m...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 48; no. 6; pp. 2009 - 2018
Main Authors Vu, CB, Pan, D, Peng, B, Kumaravel, G, Smits, G, Jin, XW, Phadke, D, Engber, T, Huang, C, Reilly, J, Tam, S, Grant, D, Hetu, G, Petter, RC
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 24.03.2005
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CVT-124
LOCALIZATION
RAT
CATALEPSY
MPTP
MONKEYS
AGONISTS
DISCOVERY
PARKINSONS-DISEASE
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Summary:Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A(2a) receptor antagonists with oral activity in rodent models of Parkinson's disease. We have replaced the piperazinyl group with a variety of linear, monocyclic, and bicyclic diamines. Of these diamines, (R)-2-(aminomethyl)pyrrolidine is a particularly potent and selective replacement for the piperazinyl group. With this diamine component, we have been able to prepare numerous analogues with low nanomolar affinity toward the A(2a) receptor and good selectivity with respect to the A(1) receptor (> 200-fold in some cases). Selected analogues from this series of [1,2,4]triazolo[1,5-a][1,3,5]triazine have now been shown to be orally active in the mouse catalepsy model.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0498396