A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

中文翻译：

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INCB24360（Epacadostat），一种用于免疫肿瘤学的强效选择性Indoleamine-2,3-dioxygenase 1（IDO1）抑制剂。

以数据为中心的药物化学方法导致了有效而选择性的IDO1抑制剂4f INCB24360（依帕卡司他）的发明。INCB24360的分子结构在原料药中包含几个以前未知或未充分利用的官能团，包括羟基am，呋喃山，溴化物和磺酰胺。这些部分以单个结构结合在一起，得到的化合物落在“类药物”空间之外。但是，体外ADME数据与在所有测试物种（大鼠，狗，猴子）中观察到的良好的细胞通透性和口服生物利用度一致。据信在4f的小分子晶体结构中观察到广泛的分子内氢键对观察到的磁导率和PK有显着贡献。