氨基甲酸酯和嘧啶可减轻酰胺水解：基于结构的四氢喹啉IDO1抑制剂药物设计
Carbamate and -Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.
作者信息
Li Derun, Deng Yongqi, Achab Abdelghani, Bharathan Indu, Hopkins Brett Andrew, Yu Wensheng, Zhang Hongjun, Sanyal Sulagna, Pu Qinglin, Zhou Hua, Liu Kun, Lim Jongwon, Fradera Xavier, Lesburg Charles A, Lammens Alfred, Martinot Theodore A, Cohen Ryan D, Doty Amy C, Ferguson Heidi, Nickbarg Elliott B, Cheng Mangeng, Spacciapoli Peter, Geda Prasanthi, Song Xuelei, Smotrov Nadya, Abeywickrema Pravien, Andrews Christine, Chamberlin Chad, Mabrouk Omar, Curran Patrick, Richards Matthew, Saradjian Peter, Miller J Richard, Knemeyer Ian, Otte Karin M, Vincent Stella, Sciammetta Nunzio, Pasternak Alexander, Bennett David Jonathan, Han Yongxin
机构信息
Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Planegg-Martinsried, Germany.
出版信息
ACS Med Chem Lett. 2021 Feb 26;12(3):389-396. doi: 10.1021/acsmedchemlett.0c00525. eCollection 2021 Mar 11.
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and -pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
吲哚胺-2,3-双加氧酶-1（IDO1）已成为癌症免疫治疗中一个有吸引力的靶点。一个自动配体识别系统筛选出了新型IDO1抑制剂的四氢喹啉类化合物。效力和药代动力学（PK）是这类化合物的关键问题。基于结构的药物设计和极性的策略性引入使得效力、溶解度和氧化代谢稳定性得到了快速改善。代谢物鉴定研究表明，D口袋中的酰胺水解是这类化合物的关键清除机制。对酰胺生物电子等排体的策略性研究表明，氨基甲酸酯和嘧啶类化合物保持了出色的效力，减轻了酰胺水解问题，并改善了大鼠的PK曲线。先导化合物是一种强效的IDO1抑制剂，具有明确的脱靶特征，并且有可能在人体中实现每日给药。
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