Therapeutic applications for novel non-hypercalcemic vitamin D receptor ligands

Background: The active form of vitamin D₃, 1α,25- dihydroxyvitamin D₃ (1,25(OH)₂D₃), plays an important role in calcium homeostasis, cell differentiation, cell proliferation and immunity. A more complete understanding of the several physiological and pharmacological properties of 1,25(OH)₂D₃ indicates that the vitamin D receptor (VDR) is a promising drug target in the treatment of cancers, autoimmune diseases, infections and cardiovascular disease as well as bone and mineral disorders. The calcemic effect of 1,25(OH)₂D ₃ and its derivatives has limited their clinical application. As a result, the development of non-calcemic VDR ligands is required to realize the potential of VDR-targeting therapy. Objective: In this review, we discuss the in vitro and in vivo pharmacological actions, including VDR interaction, regulation of cofactor recruitment, pharmacokinetics and cell type or tissue-selective action of VDR ligands with less-calcemic activity. Conclusion: Pharmacokinetic parameters and selective tissue accumulation are related to the therapeutic benefit of non-hypercalcemic vitamin D derivatives. Induction of distinct VDR conformations and cofactor recruitment may be associated with selective actions of non-secosteroidal VDR ligands. Derivatives of lithocholic acid, a newly identified endogenous VDR ligand, are less-calcemic VDR ligands.