Background: The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), 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)(2)D(3) 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)(2)D(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.