Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines

Antagonism of the adenosine A2a receptor offers great promise in the treatment of Parkinson’s disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A1) A2a antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure–activity relationships and plasma levels are described for this series.

Graphical abstractSynthetic methodology was developed for a series of 1,2,4-triazolo[1,5-c]pyrimidines of type 1. These compounds, exemplified by 16g, showed potent and selective adenosine A2A antagonist activity, as well as oral activity in a rodent model of Parkinson’s disease.Figure optionsDownload full-size imageDownload as PowerPoint slide