Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy)
vitamin D3, [developing code:
ED-71]), a new
osteoporosis treatment
drug that was recently approved in Japan, is a best-in-class
drug in the class of
calcitriol (1α,25-dihydroxyvitamin D3) and its
prodrug alfacalcidol (1α-hydroxyvitamin D3), which have been used to treat
osteoporosis for 30 years. In a comparative Phase III clinical study with
alfacalcidol in
osteoporosis patients,
eldecalcitol demonstrated superior efficacy in the endpoints of increment of bone mineral density and reduction of
bone fracture with equivalent safety to
alfacalcidol.
Eldecalcitol was discovered by searching synthetic analogs of
calcitriol and
alfacalcidol, and its main structural characteristic is having the 3-hydroxypropoxy group at the 2β-position. This review discusses why introducing the group leads to excellent efficacy and safety in
osteoporosis treatment and elucidates the functional roles of the 3-hydroxypropoxy group. Briefly, the functional roles of the group are, first, realizing the metabolism switching in which
eldecalcitol shows resistance to
CYP24A1 and is metabolized in the liver; second, increasing the affinity to the serum
carrier protein and prolonging the half-life to 53h; and third, stabilizing the
eldecalcitol-receptor complex. Taken together, these functional roles of the 3-hydroxypropoxy group are beneficial in
osteoporosis treatment. This review attempts to give a detailed account of the mode of action of
eldecalcitol by clarifying these multifunctional roles of the 3-hydroxypropoxy group from the medicinal chemist's perspective.