Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives

The (−)-(11R,2′S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A2A receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A2A receptor. These derivatives show selectivity against the A1 receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson’s disease.

Graphical abstractThe (−)-enantiomer of the antimalarial drug mefloquine is a potent and moderately selective antagonist of the adenosine A2A receptor. Further investigation of this compound has revealed a series of potent and selective keto-aryl thieno[3,2-d]pyrimidine derivatives which show promising activity in a commonly used model of Parkinson’s disease.Figure optionsDownload full-size imageDownload as PowerPoint slide