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.
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.
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DOI：
10.1021/acs.jmedchem.6b01665
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发表时间：
2017-04-13
影响因子：
7.3
通讯作者：
Wang S
中科院分区：
文献类型：
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作者：
Aguilar A;Lu J;Liu L;Du D;Bernard D;McEachern D;Przybranowski S;Li X;Luo R;Wen B;Sun D;Wang H;Wen J;Wang G;Zhai Y;Guo M;Yang D;Wang S
我们之前报道了在吡咯烷核心的碳-2位上具有两个相同取代基的螺氧吲哚作为有效的MDM2抑制剂的设计。在这篇文章中，我们描述了这类MDM2抑制剂的广泛的构效关系研究，结果发现了60个(AA-115/APG-115)。化合物60对MDM2(Ki<；1 nM)有很高的亲和力、强大的细胞活性和良好的口服药代动力学特征。化合物60能够在体内实现完全和长期的肿瘤消退，目前正在进行癌症治疗的I期临床试验。
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 (Ki < 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.