Optimization beyond AMG 232: Discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein–protein interaction

Autor:	Lawrence R. McGee, Jeffrey T. Mihalic, Yingcai Wang, Mei-Chu Lo, Jing Zhou, Steven H. Olson, Xiaoqi Chen, Frank Kayser, Jiang Zhu, Ada Chen, Jeffrey Deignan, Jonathan D. Oliner, Alexander M. Long, Daqing Sun, Ming Yu, Xin Huang, Qiuping Ye, Jiwen Jim Liu, Peter Yakowec, Julio C. Medina
Rok vydání:	2014
Předmět:	Models Molecular Scaffold Clinical Biochemistry Molecular Conformation Pharmaceutical Science Acetates Pharmacology Crystallography X-Ray Biochemistry Protein–protein interaction Structure-Activity Relationship Drug Discovery medicine Animals Humans Mdm2 p53 Molecular Biology Piperidones Sulfonamides Dose-Response Relationship Drug Chemistry Organic Chemistry Sulfonamide (medicine) Proto-Oncogene Proteins c-mdm2 Rats Molecular Medicine Drug Screening Assays Antitumor Tumor Suppressor Protein p53 Protein Binding medicine.drug
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 24:3782-3785
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2014.06.073
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cb62da92063f4e1d74dae97a63a686bb https://doi.org/10.1016/j.bmcl.2014.06.073 Zobrazit plný text záznamu Full Text from ScienceDirect