Synthesis and Biological Evaluation of Metabolites of 2‑<i>n</i>‑Butyl-9-methyl-8-[1,2,3]triazol-2-yl‑9<i>H</i>‑purin-6-ylamine (ST1535), A Potent Antagonist of the A_2A Adenosine Receptor for the Treatment of Parkinson’s Disease

The synthesis and preliminary in vitro evaluation of five metabolites of the A_2A antagonist ST1535 (<b>1</b>) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9<i>H</i>-purine (<b>2</b>) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A_2A receptor with affinities (<i>K</i>_i 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i>_i 10.7 nM), thus showing that the long duration of action of <b>1</b> could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed