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.

中文翻译：

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无环硼酸精氨酸酶抑制剂的设计与合成


精氨酸酶长期以来一直是免疫肿瘤学感兴趣的靶标，但发现口服生物可利用的抑制剂受到必要的硼酸药效团的严重限制。我们从文献抑制剂 ABH 的 β 位开始我们的药物发现活动 （1）。以 Ireland-Claisen 重排为关键步骤的分歧合成允许获得许多化合物，其中一些我们在精氨酸酶 2 的活性位点结晶。随后，我们使用基于结构的药物设计进一步提高了该系列的效力，最终实现了 IC₅₀ 值为 12 nM 的抑制剂。该系列中的许多化合物被设计为具有前药的作用，释放其有效载荷，相对于母体，口服暴露量提高了 4 倍。这些不同抑制剂和前药之间的细微立体化学差异对效力和药代动力学有重大影响。