2. Academic Validation
  3. Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction

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

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z