pgp - publications

1. J Med Chem. 2012 Mar 27. [Epub ahead of print]

Structure-Activity Relationships, Ligand Efficiency, and Lipophilic Efficiency
Profiles of Benzophenone-Type Inhibitors of the Multidrug Transporter
P-Glycoprotein.

Jabeen I, Pleban K, Rinner U, Chiba P, Ecker GF.

University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090,
Vienna, Austria.

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.

PMID: 22452412 [PubMed - as supplied by publisher]