Discovery of AM-7209, a Potent and Selective 4‑Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction

Abstract

Structure-based rational design and extensive structure–activity relationship studies led to the discovery of AMG 232 (<b>1</b>), a potent piperidinone inhibitor of the MDM2–p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of <b>1</b>, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (<b>25</b>), featuring improved potency (<i>K</i>_D from ITC competition was 38 pM, SJSA-1 EdU IC₅₀ = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED₅₀ = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED₅₀ = 10 mg/kg QD). In addition, <b>25</b> possesses distinct mechanisms of elimination compared to <b>1</b>