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

被引：170

作者：

Aguilar, Angelo ^{[1
,2
,3
,4
]}

Lu, Jianfeng ^{[1
,2
,3
,4
]}

Liu, Liu ^{[1
,2
,3
,4
]}

Du, Ding ^{[1
,2
,3
,4
]}

Bernard, Denzil ^{[1
,2
,3
,4
]}

McEachern, Donna ^{[1
,2
,3
,4
]}

Przybranowski, Sally ^{[1
,2
,3
,4
]}

Li, Xiaoqin ^{[5
]}

Luo, Ruijuan ^{[5
]}

Wen, Bo ^{[5
]}

Sun, Duxin ^{[5
]}

Wang, Hengbang ^{[6
,7
]}

Wen, Jianfeng ^{[6
,7
]}

Wang, Guangfeng ^{[6
,7
]}

Zhai, Yifan ^{[6
,7
]}

Guo, Ming ^{[6
,7
]}

Yang, Dajun ^{[6
,7
,8
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Comprehens Canc Ctr, 1600 Huron Pkwy, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, 1600 Huron Pkwy, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, 1600 Huron Pkwy, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, 1600 Huron Pkwy, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[6] Jiangsu Ascentage Biomed Dev Inc, Taizhou 225300, Jiangsu, Peoples R China

[7] Suzhou Ascentage Pharma Inc, Suzhou 215123, Jiangsu, Peoples R China

[8] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Dept Expt Res,Collaborat Innovat Ctr Canc Med, 651 Dongfeng Rd East, Guangzhou, Guangdong, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 07期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-PROTEIN INTERACTION; P53; PATHWAY; HIGHLY POTENT; ACTIVATION; MECHANISM; FLUORINE; DOCKING; DESIGN; TRIALS; RG7112;

D O I：

10.1021/acs.jmedchem.6b01665

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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-i < 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.

引用

页码：2819 / 2839

页数：21

共 35 条

[1]

Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles [J].