FXR ligands

Figure 8-10 Structures of CDCA (37), GW4064 (38), and designed FXR ligands [antagonists (39 and 40) and agonists (41 and 42)].

In such a reverse endocrinology approach the farnesoid X receptor (FXR) could be connected to bile acid ligands. By further exploration of bile acids and other chemical probes for FXR it was discovered that FXR is linked to bile acid homeostasis, and it was postulated that FXR ligands might have beneficial effects for the treatment of cholestatic liver disease and other disorders [50]. 

Ekins, S., Mirny, L. and Schuetz, E.G. (2002) A Ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR,... 

Bile acids are also natural ligands for the farnesoid X receptor (FXR), a receptor that belongs to the nuclear hormone receptor superfamily. The hydrophobic bile acid chenodeoxycholic acid (CDCA) is the most potent... 

Figure 8. Natural, non-natural and synthetic ligands for ERft, PPARy, and FXR receptors.

Because GS can be seen as a congener of PCN, it is not surprising that it can bind to PXR in addition to FXR. In contrast, its affinity to PPARa, whose natural ligand is leukotriene B4 (39, Scheme 14.10), is quite surprising. This cross-reactivity indicates that combinatorial variation of the structure of a ligand for one NR, irrespective of its scaffold (for example, steroidal or not), also leads to ligands for other NRs. 

Figure 14.4 Superposed X-ray structures of the ligand-binding domains of ERpS, PPARy, and FXR, each with bound ligand. ER(3 with genistein (41, blue), PPARy with rosiglitazone (red), FXR with 50 (yellow).

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