1410738-76-9Relevant articles and documents
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
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
, p. 2819 - 2839 (2017/04/21)
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.
