VG081821: A ZM241385‐Like A2A Receptor Antagonist With Significant Improvement in Pharmacokinetics

ZM241385 is a potent, selective A_2A receptor antagonist/inverse agonist, and has been one of the most widely used tool compounds in studies exploring the role of A_2A receptors in various conditions or probing relevant biology. However, its rapid metabolism and poor pharmacokinetic properties hindered its therapeutic use. We addressed this limitation by modifying the 4-hydroxy group on its phenyl ring, which led to the invention of VG081821. It was hypothesized that the structural modification would allow VG081821 to interact with adenosine receptors in more or less the same way. As a result, VG081821 possesses similar binding affinities and antagonistic/inverse agonistic effects on the A_2A receptor. Crucially, it possesses significantly improved metabolic stability and pharmacokinetic properties. In-vitro and in-vivo studies demonstrated VG081821's lower intrinsic clearance and superior pharmacokinetic profile compared to ZM241385. Given that more and more studies indicate that blocking A_2A receptors has multiple beneficial effects, VG081821 may have the real potential to become a clinically valuable multi-indication therapeutic agent.