4-((3'R,4'S,5'R)-6″-氯-4'-(3-氯-2-氟苯基)-1'-乙基-2″-氧代二螺[环己烷-1,2'-吡咯烷-3',3″-吲哚啉]-5'-甲酰胺基)双环[2.2.2]辛烷-1-羧酸（AA-115/APG-115）的发现：一种正在临床开发中的强效口服活性小鼠双微体2（MDM2）抑制剂。
Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.
作者信息
Aguilar Angelo, Lu Jianfeng, Liu Liu, Du Ding, Bernard Denzil, McEachern Donna, Przybranowski Sally, Li Xiaoqin, Luo Ruijuan, Wen Bo, Sun Duxin, Wang Hengbang, Wen Jianfeng, Wang Guangfeng, Zhai Yifan, Guo Ming, Yang Dajun, Wang Shaomeng
机构信息
University of Michigan Comprehensive Cancer Center, and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
出版信息
J Med Chem. 2017 Apr 13;60(7):2819-2839. doi: 10.1021/acs.jmedchem.6b01665. Epub 2017 Mar 24.
We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.
我们之前报道了在吡咯烷核心的碳-2位带有两个相同取代基的螺环氧化吲哚类化合物作为有效的MDM2抑制剂的设计。在本文中，我们描述了此类MDM2抑制剂的广泛构效关系研究，这导致了60（AA-115/APG-115）的发现。化合物60对MDM2具有非常高的亲和力（K < 1 nM），具有强大的细胞活性和出色的口服药代动力学特征。化合物60能够在体内实现完全且持久的肿瘤消退，目前正处于癌症治疗的I期临床试验阶段。
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