Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.
Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.
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DOI：
10.1021/acsmedchemlett.0c00195
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发表时间：
2020-07
影响因子：
4.2
通讯作者：
Q. Pu;Hongjun Zhang;Liangqin Guo;M. Cheng;Amy C. Doty;Heidi Ferguson;X. Fradera;C. Lesburg;Meredeth A Mcgowan;J. Miller;Prasanthi Geda;Xuelei S. Song;Karin M. Otte;N. Sciammetta;N. Solban;Wensheng Yu;D. Sloman;Hua Zhou;A. Lammens;L. Neumann;D. J. Bennett;A. Pasternak;Yongxin Han
中科院分区：
文献类型：
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作者：
Q. Pu;Hongjun Zhang;Liangqin Guo;M. Cheng;Amy C. Doty;Heidi Ferguson;X. Fradera;C. Lesburg;Meredeth A Mcgowan;J. Miller;Prasanthi Geda;Xuelei S. Song;Karin M. Otte;N. Sciammetta;N. Solban;Wensheng Yu;D. Sloman;Hua Zhou;A. Lammens;L. Neumann;D. J. Bennett;A. Pasternak;Yongxin Han
吲哚胺-2，3-双加氧酶1（IDO 1）抑制及其与免疫检查点抑制剂（如派姆单抗）的组合引起了学术界和制药行业的极大关注。在这里，我们描述了一类新型的高效IDO 1血红素置换抑制剂，具有独特的双环[1.1.1]戊烷基序的发现。从ALIS（自动化配体识别系统）命中演变的化合物1表现出优异的效力，但由于苯甲酰胺部分的广泛酰胺水解而缺乏所需的药代动力学特征。用双环[1.1.1]戊烷生物电子等排体代替1中的中心苯环有效地避免了酰胺水解问题，导致发现了具有有利的总体特征的化合物2，例如优异的效力、选择性、药代动力学和低的预测人体剂量。
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.