Novel Bicyclic Piperazine Derivatives of Triazolotriazine and Triazolopyrimidines as Highly Potent and Selective Adenosine A sub(2A) Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 47; no. 25; pp. 6218 - 6229
• Main Authors: Peng, H, Kumaravel, G, Yao, G, Sha, L, Wang, J, Van Vlijmen, H, Bohnert, T, Huang, C, Vu, C B, Ensinger, CL, Chang, H, Engber, T M, Whalley, E T, Petter, R C
• Format: Journal Article
• Language: English
• Published: 02.12.2004
• ISSN: 0022-2623
• DOI: 10.1021/jm0494321

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 sub(2a) receptor versus the adenosine A sub(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 sub(2a) antagonist 26h has a K sub(i) value of 0.2 nM and is 16 500-fold selective with respect to the A sub(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.