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

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3782-5. doi: 10.1016/j.bmcl.2014.06.073. Epub 2014 Jul 1.

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.

Keywords: MDM2; Piperidinone; Protein–protein interaction; Sulfonamide; p53.

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Piperidones / chemistry
  • Piperidones / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry

Substances

  • 2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
  • Acetates
  • Piperidones
  • Sulfonamides
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2