2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A2A antagonists with reduced hERG liability

In this report, the design and synthesis of a series of pyrimidine based adenosine A2A antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A1 are discussed. Compound 33 exhibited excellent potency, selectivity over A1, and reduced hERG liability.

Graphical abstractPyrimidine-based adenosine A2A antagonists were explored to attenuate hERG while improving A1 selectivity. Replacement of the basic amine side chain led to potent and selective A2A antagonists, with reduced hERG liability.Figure optionsDownload full-size imageDownload as PowerPoint slide