Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors

Arginase has long been a target of interest in immuno-oncology,
but discovering an orally bioavailable inhibitor is severely constrained
by the requisite boronic acid pharmacophore. We began our drug discovery
campaign by building off the β-position of the literature inhibitor
ABH (1). A divergent synthesis with an Ireland–Claisen
rearrangement as the key step allowed access to numerous compounds,
some of which we crystallized in the active site of arginase 2. We
subsequently used structure-based drug design to further improve the
potency of this series, ultimately achieving an inhibitor with an
IC50 value of 12 nM. Many compounds in this series were
designed to behave as prodrugs, releasing their payload with up to
4-fold improved oral exposure relative to the parent. Subtle stereochemical
differences between these various inhibitors and prodrugs had substantial
effects on potency and pharmacokinetics.