Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists.

1α,25-Dihydroxyvitamin D [1α,25(OH)D, ] is an active form of vitamin D and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, ) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative () is a more potent agonist than 1α,25(OH)D, (), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of with amino acid residues in the VDR ligand-binding pocket.

Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.

Lithocholic acid () was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to . Among the synthesized compounds, bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid () and 3 times more potent than 1α,25-dihydroxyvitamin D ().