Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A2A receptor antagonists
| Autor: | Thomas Engber, Tonika Bohnert, Herman W. T. van Vlijmen, Ensinger Carol L, Gang Yao, Gnanasambandam Kumaravel, Petter Russell C, Li Sha, Eric T. Whalley, Joy Wang, Carol Huang, Hexi Chang, Hairuo Peng, Chi Vu |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Pyrazine Stereochemistry Adenosine A2A receptor Administration Oral Catalepsy In Vitro Techniques Chemical synthesis Piperazines Rats Sprague-Dawley Adenosine A1 receptor chemistry.chemical_compound Mice Radioligand Assay Structure-Activity Relationship Drug Stability Drug Discovery medicine Animals Bicyclic molecule Molecular Structure Triazines Antagonist Parkinson Disease Stereoisomerism Triazoles medicine.disease Adenosine A2 Receptor Antagonists Rats Piperazine Disease Models Animal Pyrimidines chemistry Microsomes Liver Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 47(25) |
| ISSN: | 0022-2623 |
| Popis: | 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 26 h has a K(i) value of 0.2 nM and is 16 500-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. |
| Databáze: | OpenAIRE |
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