Lithocholic acid-based design of noncalcemic vitamin D receptor agonists

[Display omitted] •In silico design and efficient stereoselective synthesis of six lithocholic acid derivatives (2E, 2Z, 3a, 3b, 4a, and 4b).•All compounds bind to hVDR with lower affinity compared to 1,25D, 4a showing the highest affinity.•Compound 4a was the most active in biological tests.•4a has low calcemic activity.•Crystal structure analysis uncovers binding mode of 4a with zVDR ligand binding domain. The hypercalcemic effects of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.