title: Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.
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.
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ada
authors.initials: A
authors.lastname: Chen
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: John
authors.initials: J
authors.lastname: Eksterowicz
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Fox
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Fu
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gribble
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jiwen Jim
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Mei-Chu
authors.initials: MC
authors.lastname: Lo
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Dustin
authors.initials: D
authors.lastname: McMinn
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Shaffer
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Dongyin
authors.initials: D
authors.lastname: Yu
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
keywords: MDM2; p53; piperidinone; protein−protein interaction; pyridine