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

Ishrat Jabeen, Karin Pleban, Uwe Rinner, Peter Chiba, Gerhard F. Ecker

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3261-3273
Number of pages13
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
Publication statusPublished - Apr 12 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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