Discovery of Selective and Orally Available Galectin‑1 Inhibitors

A new
series of orally available α-d-galactopyranosides
with high affinity and specificity toward galectin-1 have been discovered.
High affinity and specificity were achieved by changing six-membered
aryl-triazolyl substituents in a series of recently published galectin-3-selective
α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles
such as thiazoles. The in vitro pharmacokinetic properties were optimized,
resulting in several galectin-1 inhibitors with favorable properties.
One compound, GB1490 (Kd galectin-1/3
0.4/2.7 μM), was selected for further characterization toward
a panel of galectins showing a selectivity of 6- to 320-fold dependent
on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals
the compound bound in a single conformation in the carbohydrate binding
site. GB1490 was shown to reverse galectin-1-induced apoptosis of
Jurkat cells at low μM concentrations. No cell cytotoxicity
was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic
studies in mice, GB1490 showed high oral bioavailability (F% > 99%).