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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.

ABSTRACT: 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.

SUBMITTER: Aguilar A 

PROVIDER: S-EPMC5394527 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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 A   Lu Jianfeng J   Liu Liu L   Du Ding D   Bernard Denzil D   McEachern Donna D   Przybranowski Sally S   Li Xiaoqin X   Luo Ruijuan R   Wen Bo B   Sun Duxin D   Wang Hengbang H   Wen Jianfeng J   Wang Guangfeng G   Zhai Yifan Y   Guo Ming M   Yang Dajun D   Wang Shaomeng S  

Journal of medicinal chemistry 20170324 7

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<sub>i</sub> < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete  ...[more]

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