Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton

•Novel VDR agonists with phenyl-pyrrolyl pentane skeleton were synthesized.•Compound 2g showed more potent VDR agonistic activity than tacalcitol.•Compound 2g had no effect on serum calcium.

In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl–pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC50: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC50: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC50 of 2.06 μM and 0.307 μM (tacalcitol: 2.07 μM and 0.057 μM) and showed no significant effect on serum calcium.

Graphical abstractCompound 2g (EC50: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC50: 7.05 nM).Figure optionsDownload full-size imageDownload as PowerPoint slide