Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P-glycoprotein

J Med Chem. 2012 Apr 12;55(7):3261-73. doi: 10.1021/jm201705f. Epub 2012 Mar 27.

Abstract

The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P-glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Benzophenones / chemical synthesis*
  • Benzophenones / chemistry
  • Benzophenones / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Propafenone / analogs & derivatives
  • Propafenone / chemical synthesis
  • Propafenone / chemistry
  • Propafenone / pharmacology
  • Quantitative Structure-Activity Relationship
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Benzophenones
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Ligands
  • Serotonin Plasma Membrane Transport Proteins
  • Propafenone