Discovery of 4-((3′R4′S5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispirocyclohexane-12′-pyrrolidine-3′3″-indoline-5′-carboxamido)bicyclo2.2.2octane-1-carboxylicAcid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute2 (MDM2) Inhibitor in Clinical Development

摘要

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.