Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A(2A) receptor antagonists

A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure-activity-relationship (SAR) studies based on octahy...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 47; no. 25; pp. 6218 - 6229
Main Authors Peng, HR, Kumaravel, G, Yao, G, Sha, L, Wang, J, Van Vlijmen, H, Bohnert, T, Huang, C, Vu, CB, Ensinger, CL, Chang, HX, Engber, TM, Whalley, ET, Petter, RC
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 02.12.2004
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CATALEPSY
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Summary:A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure-activity-relationship (SAR) studies based on octahydropyrrolo[1,2-a]pyrazine and octahydropyrido[1,2-a]pyrazine with various capping groups are reported. Among these analogues, the most potent and selective A(2a) antagonist 26h has a K-i value of 0.2 nM and is 16500-fold selective with respect to the A(1) receptor. Among a number of compounds tested, compounds 21a and 21c exhibited significantly improved metabolic stability. Compounds 21a, 21c, and 18a showed good oral efficacy in rodent catalepsy models of Parkinson's disease.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0494321