Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

“…For example, obeticholic acid (i.e., INT-747), a potent selective FXR agonist, is in phase III trials for primary biliary cirrhosis (Pellicciari et al, 2005). Also, the hepatoprotective effects of GW4064 and its analogs have been shown in cholestatic rats and mice with gallstones (Liu et al, 2003;Moschetta et al, 2004;Akwabi-Ameyaw et al, 2008;Bass et al, 2011;Porez et al, 2012). Our results suggest that drugdrug interactions between CYP2D6 substrates and FXR agonists may occur if these FXR agonists are approved and clinically used.…”

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…However, GW4064 presents some major pharmacodynamic limitations: a certain toxicity due to the stilbene moiety, a poor bioavailability, and the diffi culty to target extrahepatic tissues due to fast metabolism by the liver. Thus, quite an effort has been made to develop GW4064 analogs with comparable potency and improved biological compatibility ( 116,117 ); however, none has yet passed preclinical testing. In addition, a number of GW4064 analogs are handled by BA transporters and conjugated like BA, leading to very low plasma levels and hepatic accumulation ( 118 ).…”

Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease

“…The structure of the FXR protein bound to GW4064 was used as the docking target (PDB ID: 3DCT). 34 Using this approach, 6EUDCA, UDCA, and GW4064 were predicted to share the same FXR binding pocket ( Figure 8A and 8B), which is formed by M265, M290, R331, H447, W469, etc. 6EUDCA contacts more closely with the surface of FXR than that of UDCA.…”