Chapter 5

Recent Developments of P-gp Inhibitors

Sören Krawczyk, Christiane Baumert and Andreas Hilgeroth


Multidrug resistance (MDR) plays the central role in failing cancer therapy regimes of today. The MDR phenomenon concerns various drugs of structurally related as well as unrelated compound classes including also novel anticancer drugs. Formerly drug-sensitive cancer cells lose their sensitivity and become resistant under theapy. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug efflux pumps that lowers the intracellular drug levels by an active drug transport out of the cells. P-glycoprotein (P-gp) is the longest identified efflux pump. The attempt to overcome the MDR phenomenon by the use of inhibitors of the efflux pump activities turned out as most promising beside other so far non-effective tries. So far there exists no X-ray crystal structure analysis of P-gp which is difficult to crystallize because of its transmembrane protein character. Thus, the development of Pgp inhibitors has been a challenge for medicinal chemists. The article reviews advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements up today. One success has been the reduction of cytotoxic properties partly resulting from the originally pharmacological compound properties. However, undesired drug interactions and resulting toxicities limited clinical in vivo activities so far.

Total Pages: 184-239 (56)

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