Design and\nSynthesis of Acyclic Boronic Acid Arginase\nInhibitors

Arginase has long been a target of interest in immuno-oncology,\nbut discovering an orally bioavailable inhibitor is severely constrained\nby the requisite boronic acid pharmacophore. We began our drug discovery\ncampaign by building off the β-position of the literature inhibitor\nABH (<b>1</b>). A divergent synthesis with an Ireland–Claisen\nrearrangement as the key step allowed access to numerous compounds,\nsome of which we crystallized in the active site of arginase 2. We\nsubsequently used structure-based drug design to further improve the\npotency of this series, ultimately achieving an inhibitor with an\nIC<sub>50</sub> value of 12 nM. Many compounds in this series were\ndesigned to behave as prodrugs, releasing their payload with up to\n4-fold improved oral exposure relative to the parent. Subtle stereochemical\ndifferences between these various inhibitors and prodrugs had substantial\neffects on potency and pharmacokinetics.