title: Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P-glycoprotein.
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.
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090, Vienna, Austria.
authors.forename: Ishrat
authors.initials: I
authors.lastname: Jabeen
authors.forename: Karin
authors.initials: K
authors.lastname: Pleban
authors.forename: Uwe
authors.initials: U
authors.lastname: Rinner
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011405:Propafenone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001577:Benzophenones; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D050486:Serotonin Plasma Membrane Transport Proteins; D011405:Propafenone