Synthesis and discovery of andrographolide derivatives as non-steroidal farnesoid X receptor (FXR) antagonists

Based upon the discovery of the natural compound andrographolide (1) as a non-steroidal farnesoid X receptor (FXR) antagonist, a series of andrographolide derivatives were designed and synthesized accordingly. Our primary SAR studies demonstrated that 14-phenoxy andrographolide scaffold is an excellent structural pharmacophore for FXR antagonists. Remarkably, 14β-compounds of 12b, 12f and 10g were found to be the most potent FXR antagonists in this work. Structural docking discovered that the phenoxy substitution at the 14-position and the modification at 3,19-positions altered the putative binding positions of small FXR ligands, resulting in their FXR antagonistic activity discrepancy. This journal is