Synthesis and Biological Evaluation of Metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-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 (1) are reported. The metabolites, originating in vivo from enzymatic oxidation of 2-butyl group of parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9H-purine (2) by selective C-C bond formation via halogen/magnesium exchange and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist, ligands of cloned human A(2A), receptor with affinities (K-i 7.5-53 nM) comparable to that of compound 1 (K-i 10.7 nM), thus showing that the long duration of action of 1 could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed.