Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development

We recently reported the discovery of AM-8553 (<b>1</b>), a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Continued research investigation of the <i>N</i>-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (<b>2</b>), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound <b>2</b> is an extremely potent MDM2 inhibitor (SPR <i>K</i>_D = 0.045 nM, SJSA-1 EdU IC₅₀ = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED₅₀ = 9.1 mg/kg)