Combined effort for cholesterol

New drugs for lipid disorders might be on the horizon thanks to new work on the transcriptional sensor FXR (farnesoid X receptor). FXR senses bile acids, the metabolic products of the notorious steroid cholesterol, a novel agonist, fexaramine, found by US researchers, has 100 times the affinity of natural compounds.

Ronald Evans

K.C. Nicolaou

High levels of cholesterol are associated with atherosclerosis, a major risk factor for heart disease and stroke so the development of potent and selective compounds that interact with FXR could play an important role in unravelling cholesterol and lipid metabolism and ultimately lead to new therapies. An agonist to FXR would essentially shut off bile acid production slowing the emulsification and absorption of many fats. As such several teams are in hot pursuit of FXR agonists and antagonists.

Kyriacos "KC" Nicolaou of the Scripps Research Institute and UCSD and Ronald Evans of the Salk Institute have used a cell-based reporter assay to screen a 10,000 member library, which revealed several high affinity agonists. (Org. Biomol. Chem., 2003, 1(6), 908-920; http://dx.doi.org/10.1039/b300525a). They report the profile of the most potent, fexaramine, in Molecular Cell [2003 11(4), 1079-1092; http://www.molecule.org/content/article/abstract?
uid=PIIS1097276503001333]. "Fexaramine will allow us to unravel the FXR genetic network from the bile acid network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol related human diseases," says Evans.

Alan Tall

David Mangelsdorf

The natural ligands for FXR and other lipid-sensing receptors are toxic at high concentration, adds David Mangelsdorf of the University of Texas Southwestern Medical Centre, so screening combinatorial chemistry libraries is a good way to identify non-toxic activators. "FXR agonists have strong potential as triglyceride-lowering agents in addition to their ability to lower cholesterol," adds Alan Tall of Columbia University, "this might allow them to be used effectively as supplements to statin drugs."