Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1983-6. doi: 10.1016/j.bmcl.2014.02.055. Epub 2014 Feb 28.

Abstract

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.

Keywords: Cancer; HDM2; Protein–protein interaction; p53.

MeSH terms

  • Biological Assay
  • Cell Proliferation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Piperidines
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2