Pu Qinglin, Zhang Hongjun, Guo Liangqin, Cheng Mangeng, Doty Amy C, Ferguson Heidi, Fradera Xavier, Lesburg Charles A, McGowan Meredeth A, Miller J Richard, Geda Prasanthi, Song Xuelei, Otte Karin, Sciammetta Nunzio, Solban Nicolas, Yu Wensheng, Sloman David L, Zhou Hua, Lammens Alfred, Neumann Lars, Bennett David Jonathan, Pasternak Alexander, Han Yongxin
Boston Discovery Chemistry, Therapeutic Modalities, Quantitative Biosciences, Discovery Pharm Science Boston/Westpoint, Computational & Structural Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
External Discovery Chemistry, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
ACS Med Chem Lett. 2020 Jul 15;11(8):1548-1554. doi: 10.1021/acsmedchemlett.0c00195. eCollection 2020 Aug 13.
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like 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 , 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 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
吲哚胺-2,3-双加氧酶1（IDO1）抑制作用及其与免疫检查点抑制剂的联合应用已引起学术界和制药行业的广泛关注。在此，我们描述了一类新型的高效IDO1血红素置换抑制剂的发现，其具有独特的双环[1.1.1]戊烷基序。化合物 由自动配体识别系统（ALIS）筛选得到，显示出优异的活性，但由于苯甲酰胺部分的广泛酰胺水解，缺乏理想的药代动力学特征。用双环[1.1.1]戊烷生物电子等排体取代 中的中心苯环有效地规避了酰胺水解问题，从而发现了化合物 ，其具有良好的综合特性，如优异的活性、选择性、药代动力学和低预测人体剂量。
