Studies on Pyrrolopyrimidines as Selective Inhibitors of Multidrug-Resistance- Associated Protein in Multidrug Resistance
Citations Over TimeTop 14% of 2004 papers
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.
Related Papers
- → Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells(2019)27 cited
- → Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors(1990)70 cited
- → Reversal of Multidrug Resistance by 7-O-Benzoylpyripyropene A in Multidrug-Resistant Tumor Cells.(2000)14 cited
- → Expression of multidrug resistance (P‐glycoprotein) gene in liver cancers(1993)
- Progress in anti-multidrug resistance mediated by p-glycoprotein(2006)