Yue Eddy W, Sparks Richard, Polam Padmaja, Modi Dilip, Douty Brent, Wayland Brian, Glass Brian, Takvorian Amy, Glenn Joseph, Zhu Wenyu, Bower Michael, Liu Xiangdong, Leffet Lynn, Wang Qian, Bowman Kevin J, Hansbury Michael J, Wei Min, Li Yanlong, Wynn Richard, Burn Timothy C, Koblish Holly K, Fridman Jordan S, Emm Tom, Scherle Peggy A, Metcalf Brian, Combs Andrew P
Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
ACS Med Chem Lett. 2017 Mar 6;8(5):486-491. doi: 10.1021/acsmedchemlett.6b00391. eCollection 2017 May 11.
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor , 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 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 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.
以数据为中心的药物化学方法促成了一种强效且选择性的吲哚胺2,3-双加氧酶1（IDO1）抑制剂INCB24360（依帕司他）的发明。INCB24360的分子结构包含药物中几个先前未知或未充分利用的官能团，包括羟脒、呋咱、溴化物和磺酰胺。这些部分共同存在于单一结构中，得到了一种不属于“类药物”空间的化合物。然而，药代动力学数据与在所有测试物种（大鼠、狗、猴子）中观察到的良好细胞通透性和口服生物利用度一致。据信，在该小分子晶体结构中观察到的广泛分子内氢键显著有助于所观察到的通透性和药代动力学。依帕司他与抗PD1单克隆抗体帕博利珠单抗联合用药目前正在不可切除或转移性黑色素瘤患者的3期临床试验中进行研究。
