Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists

Abstract

Lithocholic acid (<b>2</b>) 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 <b>2</b>. Among the synthesized compounds, <b>6</b> bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of <b>2</b> showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid (<b>2</b>) and 3 times more potent than 1α,25-dihydroxyvitamin D₃ (<b>1</b>). Although the binding affinities of <b>6</b> and its epimer <b>7</b> were less than that of <b>1</b>, their transactivation activities were greater than that of <b>1</b>. X-ray structure analyses of VDR LBD bound to <b>6</b> or <b>7</b> showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of <b>1</b>.