Piperazine Derivatives of [1,2,4]Triazolo[1,5-<i>a</i>][1,3,5]triazine as Potent and Selective Adenosine A₂_aReceptor Antagonists

Abstract

The [1,2,4]triazolo[1,5- a ]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A 2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5- a ]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A 2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3 . The selectivity level over the adenosine A 1 receptor subtype for some of the more active analogues is also fairly high, >400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5- a ]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35 ). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5- a ]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.