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Parkinson’s disease (PD) is a neurodegenerative disease with significant unmet medical needs. The current dopamine-centered treatments aim to restore motor functions of patients without slowing the disease progression. Long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinesia. Furthermore, the nonmotor features associated with PD such as sleep disorder, pain, and psychiatric symptoms are poorly addressed by the dopaminergic treatments. Adenosine receptor A2A antagonists have emerged as potential treatment for PD in the past decade. Here we summarize the recent work (2015–2018) on adenosine receptor A2A antagonists and discuss the challenge and opportunity for the treatment of PD.

Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson’s disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson’s disease.