Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators

The vitamin D receptor (VDR), a receptor for the secosteroid 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], is a promising drug target in the treatment of bone and mineral disorders, cancer, autoimmune disease, infection, and cardiovascular disease. Indeed, approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed. Analysis of X-ray crystal structures reveals: (i) nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25(OH)(2)D-3; (ii) hydrogen bond interactions between ligands and VDR are the most important for VDR binding; (iii) hydrophobic interactions and CH-pi interactions in aromatic ligands are also important for VDR binding; and (iv) exchange of C-O-C linkage to C-CH2-C linkage in VDRMs increases transactivation activity, probably as a result of an entropic effect of solvation/desolvation of molecules. Several VDRMs have better therapeutic efficacy when compared to 1,25(OH)(2)D-3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a Major potential adverse effect in the clinical application of VDR ligands.