9. The Systems Biology of Transporters – Targeting the Regulatory System for Transporters (FXR/RXR)

This chapter begins with the pharmacological characterization of farnesoid X receptor (FXR) as well as a thorough description of the mechanisms by which the receptor regulates the hepatobiliary transport system. Then, it provides the reader with a description of the substantial medicinal chemistry efforts that have resulted in the discovery of several classes of ligands capable to bind and modulate the functions of the receptor. FXR adopts direct and indirect mechanisms to regulate the transcriptional expression of major carrier proteins of the hepatobiliary transport system. In this context, the relevance of FXR-mediated mechanisms is sustained by a recent work showing that the bile acid (BA)-mediated activation of FXR triggers the expression of the hepatobiliary transporters just after birth in newborn mice, thereby contributing to the maturation of the enterohepatic circulation in the neonatal period. Beside high-throughput screening approaches, virtual screening was pursued as a viable strategy to discover nonsteroidal ligands of FXR.