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. Here, we designed and synthesized amide derivatives of in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the -cyanoamide is more active than either or .