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

• DOI: 10.1021/acs.jmedchem.6b01665
• Publication Date: 2017-03-25T13:59:23Z
• Authors: 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
• Keywords: Osteosarcoma; Indoles; Leukemia; Pyrrolidines; Halogenation; Antineoplastic Agents; Bone Neoplasms; Proto-Oncogene Proteins c-mdm2; 01 natural sciences; Bone and Bones; Rats; 0104 chemical sciences; 3. Good health; Molecular Docking Simulation; Bridged Bicyclo Compounds; Mice; Structure-Activity Relationship; Cell Line, Tumor; Neoplasms; Drug Discovery; Animals; Humans

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.