title: Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.
abstract: We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: jiangz@amgen.com.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jiwen Jim
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Mihalic
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deignan
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Mei-Chu
authors.initials: MC
authors.lastname: Lo
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D010881:Piperidones; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Piperidinone; Protein–protein interaction; Sulfonamide; p53