Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists

To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 × 1 mg/kg/day upon oral administration.

Graphical abstractTo overcome the known liabilities of GW4064 a series of analogues were synthesized with increased potency in vitro and with superior lipid lowering effects in db/db mice compared to 6-ethyl-CDCA.Figure optionsDownload full-size imageDownload as PowerPoint slide