Structure-based design of novel inhibitors of the MDM2-p53 interaction

  • J Med Chem. 2012 Jun 14;55(11):4936-54. doi: 10.1021/jm300354j.
Yosup Rew  1 ,  Daqing Sun ,  Felix Gonzalez-Lopez De Turiso ,  Michael D Bartberger ,  Hilary P Beck ,  Jude Canon ,  Ada Chen ,  David Chow ,  Jeffrey Deignan ,  Brian M Fox ,  Darin Gustin ,  Xin Huang ,  Min Jiang ,  Xianyun Jiao ,  Lixia Jin ,  Frank Kayser ,  David J Kopecky ,  Yihong Li ,  Mei-Chu Lo ,  Alexander M Long ,  Klaus Michelsen ,  Jonathan D Oliner ,  Tao Osgood ,  Mark Ragains ,  Anne Y Saiki ,  Steve Schneider ,  Maria Toteva ,  Peter Yakowec ,  Xuelei Yan ,  Qiuping Ye ,  Dongyin Yu ,  Xiaoning Zhao ,  Jing Zhou ,  Julio C Medina ,  Steven H Olson
Affiliations
  • 1. Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 22524527 DOI: 10.1021/jm300354j
Abstract

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 Inhibitor with excellent pharmacokinetic properties and in vivo efficacy.