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.
基金：
National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA121279]; National Cancer Institute Cancer Center Core grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA046592]; Ascentage Pharma Group to the University of Michigan; Key New Drug Creation project of the major science and technology program, China [2012ZX09401005]; National 863 Grant, China [2012AA020305]; Science & Technology Innovation Team Grant of Guangdong Province [2013Y114]
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|2 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[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;
通讯作者：
通讯机构：[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;
推荐引用方式(GB/T 7714)：
Aguilar Angelo,Lu Jianfeng,Liu Liu,et al.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[J].JOURNAL OF MEDICINAL CHEMISTRY.2017,60(7):2819-2839.doi:10.1021/acs.jmedchem.6b01665.
APA：
Aguilar, Angelo,Lu, Jianfeng,Liu, Liu,Du, Ding,Bernard, Denzil...&Wang, Shaomeng.(2017).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.JOURNAL OF MEDICINAL CHEMISTRY,60,(7)
MLA：
Aguilar, Angelo,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 60..7(2017):2819-2839
医学