Recent Developments of 19-Nor-1,25-dihydroxyvitamin D3 Analogues

The vitamin D hormone, 1 alpha,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)(2)D-3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. D-2(3) have suggested a multitude of potential therapeutic applications for the vitaminD hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)(2)D(3)hypercalcemia, increased bone resorption, and soft tissue calcificationlimit the use of the natural ligand in these clinical applications. D-2(3) analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. (3) derivatives that lack the ring-A exocyclic methylene group (C19). In this review, the 19-nor-1,25(OH)(2)D-3 analogues are classified according to modifications made at the A-ring, the side chain, or both the A-ring and side chain, as well as other positions. D-2(3) analogues are summarized and their structure-activity relationships and binding features with the vitaminD receptor (VDR) are discussed.