Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout

To test the hypothesis that inhibitors
of human concentrative nucleoside
transporter 2 (hCNT2) suppress increases in serum urate levels derived
from dietary purines, we previously identified adenosine derivative 1 as a potent hCNT2 inhibitor (IC50 = 0.64 μM),
but further study was hampered due to its poor solubility. Here we
describe the results of subsequent research to identify more soluble
and more potent hCNT2 inhibitors, leading to the discovery of the
benzimidazole nucleoside 22, which is the most potent
hCNT2 inhibitor (IC50 = 0.062 μM) reported to date.
Compound 22 significantly suppressed the increase in
plasma uric acid levels after oral administration of purine nucleosides
in rats. Because compound 22 was poorly absorbed orally
in rats (F = 0.51%), its pharmacologic action was
mostly limited to the gastrointestinal tract. These findings suggest
that inhibition of hCNT2 in the gastrointestinal tract can be a promising
approach for the treatment of hyperuricemia.