Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction

  • ACS Med Chem Lett. 2014 Jun 30;5(8):894-9. doi: 10.1021/ml500142b.
Ming Yu  1 ,  Yingcai Wang  1 ,  Jiang Zhu  1 ,  Michael D Bartberger  2 ,  Jude Canon  2 ,  Ada Chen  1 ,  David Chow  1 ,  John Eksterowicz  1 ,  Brian Fox  1 ,  Jiasheng Fu  1 ,  Michael Gribble  1 ,  Xin Huang  3 ,  Zhihong Li  1 ,  Jiwen Jim Liu  1 ,  Mei-Chu Lo  1 ,  Dustin McMinn  1 ,  Jonathan D Oliner  2 ,  Tao Osgood  2 ,  Yosup Rew  1 ,  Anne Y Saiki  2 ,  Paul Shaffer  3 ,  Xuelei Yan  1 ,  Qiuping Ye  1 ,  Dongyin Yu  2 ,  Xiaoning Zhao  1 ,  Jing Zhou  1 ,  Steven H Olson  1 ,  Julio C Medina  1 ,  Daqing Sun  1
Affiliations
  • 1. Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • 2. Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 3. Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 25147610 DOI: 10.1021/ml500142b
Abstract

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.

Keywords
MDM2; p53; piperidinone; protein−protein interaction; pyridine.