posted on 2020-03-13, 18:37authored byRoman Blaszczyk, Joanna Brzezinska, Barbara Dymek, Paulina S. Stanczak, Marcin Mazurkiewicz, Jacek Olczak, Julita Nowicka, Karolina Dzwonek, Agnieszka Zagozdzon, Jakub Golab, Adam Golebiowski
We designed and synthesized a series
of arginase inhibitors as
derivatives of the well-known 2-(S)-amino-6-boronohexanoic
acid (ABH) with basic and neutral side chains in the α-position
relative to the amino acid group. In an effort to improve the pharmacokinetic
profile of literature examples and retain potent enzymatic activity,
sulfamido moieties were introduced to generate hydrogen bond interaction
with the aspartic acid residue in the arginase active site. The compounds
with basic guanidine-containing side chains were even more potent
arginase inhibitors. Both groups of compounds, as designed, demonstrated
low clearance in their pharmacokinetic profile. The most active inhibitor 15aa showed high nanomolar potency with IC50 =
32 nM toward human arginase 1 and demonstrated low clearance (4.2
mL/min/kg), long t1/2, and moderate volume
of distribution in rat pharmacokinetic studies.