A-ring analogs of 1,25-dihydroxyvitamin D3

The growing interest in1α,25(OH)2D3, the hormonally active form of vitamin D3, has prompted numerous efforts to synthesize vitamin D analogs as potential therapeutic agents, and some of these are already on the market and in clinical development. Although most vitamin D preparations developed thus far have focused on side-chain modifications, providing many useful analogues with high potency and selectivity, in recent years, modifications of the A-ring has attracted much attention because it can afford useful analogues exhibiting unique activity profiles as well. In this review we will focus on the current understanding of the relationship between selected modifications in the A-ring of the 1α,25(OH)2D3 molecule, such as epimerization and/or substitution at C-1 and C-3, substitution at C-2, and removal of the 10,19-exocyclic methylene group, and their effect on biological potency and selectivity. Finally, suggestions for the structure-based design of therapeutically valuable A-ring vitamin D analogs will conclude the review.