In search for FXR gene selective modulators: synthesis, biological activity and docking studies of 23-N-carbocinnamyloxy-norchenodeoxycholanylamine (UPF838).

The discovery of modulators for the Farnesoid X Receptor (FXR) has recently attracted a considerable interest in view of the therapeutic opportunities offered by this bile acid sensor in the area of bile acid and cholesterol related human diseases. While a number of potent and selective FXR agonists have already been reported, with the semi-synthetic bile acid 6-ECDCA (INT747) already in Phase I clinical studies, less is known on FXR partial agonists and antagonists. Herein, we report that carbamate derivatives of 3alpha,7alpha-dihydroxy-24-nor-5beta-cholan-23-amine represent a novel class of FXR partial agonists endowed with favourable gene selective modulating properties. One of them, in particular, UPF838 has been shown to induce BSEP, whose increased expression is potentially useful in cholestasic diseases, and to not induce SHP, another FXR target gene known to be responsible for the undesired triglycerides level increase. Docking results have revealed that the side chain of the UPF838 almost perfectly fits a so far unexploited receptor cavity localized near the ‘back door’ of FXR. Thus, for the first time we demonstrate that a fine tuned modulation of FXR can be achieved by modifying a part of the molecule (i.e. the extended side chain) which is predicted to not directly affect the H12 orientation. The significance of this observation may be of great relevance towards the design of selective FXR modulators (SBARMs) and can in principle be extended to other members of the nuclear receptor superfamily.