jm6b01665_si_001.csv (6.4 kB)

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

Download (6.4 kB)
posted on 24.03.2017, 16:52 by Angelo Aguilar, Jianfeng Lu, Liu Liu, Ding Du, Denzil Bernard, Donna McEachern, Sally Przybranowski, Xiaoqin Li, Ruijuan Luo, Bo Wen, Duxin Sun, Hengbang Wang, Jianfeng Wen, Guangfeng Wang, Yifan Zhai, Ming Guo, Dajun Yang, Shaomeng Wang
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.