ABSTRACT
Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.
Subject(s)
Drug Resistance, Multiple , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Animals , Area Under Curve , Biological Availability , Biological Transport , Cell Line, Tumor , Combinatorial Chemistry Techniques , Daunorubicin/metabolism , Daunorubicin/pharmacology , Drug Synergism , Female , Half-Life , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Multidrug Resistance-Associated Proteins/biosynthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
