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

The vitamin D hormone, 1α,25‐dihydroxyvitamin D3 [1,25‐(OH)2D3], 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)2D3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)2D3 have suggested a multitude of potential therapeutic applications for the vitamin D 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)2D3—hypercalcemia, increased bone resorption, and soft tissue calcification—limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)2D3 analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19‐nor‐vitamin D3 derivatives that lack the ring‐A exocyclic methylene group (C19). In this review, the 19‐nor‐1,25(OH)2D3 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. The biological activities of these 19‐nor‐1,25(OH)2D3 analogues are summarized and their structure–activity relationships and binding features with the vitamin D receptor (VDR) are discussed. Vital analogues: The use of 1,25(OH)2D3 for the treatment of a wide variety of diseases was limited by the parallel induction of hypercalcemic effects. There is an urgent need to find novel agents with greater selectivity. This review highlights recent advances in the research of 19‐nor‐1,25‐dihydroxyvitamin D3 analogues, paying special attention to their activities and structure– activity relationships.