Vitamin D analogues

The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases, immune dysfunction, endocrine disorders, and metabolic bone disease. However, the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases. New vitamin D analogues are under development that display greater specificity, in most cases, by retaining the therapeutic properties of 1,25(OH)2D3, but with lower calcemic activity. Two analogues have been approved for use in patients: calcipotriol (Dovonex from Leo Pharmaceuticals, Copenhagen, Denmark) for the treatment of psoriasis; and 19-nor-1,25(OH)2D2 (Zemplar from Abbott Laboratories, Abbott Park, IL) for secondary hyperparathyroidism. Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis, and for immunosuppression. The selectivity of the analogues can be attributed to the combined interactions with four proteins: the vitamin D receptor (VDR), the serum vitamin D binding protein (DBP), the vitamin D-24-hydroxylase and to a newly described membrane receptor. Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol (OCT), which is being tested for secondary hyperparathyroidism. However, the low calcemic activity of other analogues, including 19-nor-1,25(OH)2D2, involves other, as yet undefined, mechanisms. Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders.