Discovery of Novel Dual Adenosine A 2A and A 1 Receptor Antagonists with 1 H -Pyrazolo[3,4 -d ]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents.

New compounds with 1 H -pyrazolo [3,4 -d ]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A 2A and A 1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities ( h A 2A K i = 13.3 nM; h A 1 K i = 55 nM) and full antagonism ( h A 2A IC 50 = 136 nM; h A 1 IC 50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson's disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED 50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A 2A /A 1 receptor antagonist, 11o , is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.