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<sub>2A</sub> Adenosine Receptor for the Treatment of Parkinson’s
Disease
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Abstract
The
synthesis and preliminary in vitro evaluation of five metabolites
of the A<sub>2A</sub> 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<sub>2A</sub> receptor with affinities (<i>K</i><sub>i</sub> 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i><sub>i</sub> 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