Discovery of 1,2,4-Triazine Derivatives as Adenosine A_2A Antagonists using Structure Based Drug Design

Abstract

Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A_2A receptor. The X-ray crystal structures of compounds <b>4e</b> and <b>4g</b> bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound <b>4k</b> are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson’s disease