The development of a bone- and parathyroid-specific analog of vitamin D: 2-methylene-19-Nor-(20S)-1α,25-dihydroxyvitamin D3

Abstract

The goal of synthetic chemists in the vitamin D field has been to produce an analog(s) of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) that is selective for a specific function. The accumulation of structure/function information has led to the synthesis of two analogs that are both selective and more potent than 1,25-(OH)2D3, that is, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) and 2α-methyl-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2AMD). In vivo, the efficacy of 2MD is approximately equal to that of 1,25-(OH)2D3 in intestinal calcium transport but is 30- to 100-fold more active in bone mobilization. In vitro, 2MD supports new bone synthesis at 10(-12) M, whereas 1,25-(OH)2D3 is active at 10(-8) M. Similarly, 2MD is two orders of magnitude more potent than 1,25-(OH)2D3 in stimulating osteoclastogenesis and osteoclastic bone resorption. 2MD also markedly increases bone mass and bone strength of ovariectomized female rats. In postmenopausal women, 2MD significantly increases markers of both bone formation and resorption but has minimal effect on bone mass. Thus, in patients who are undergoing primarily remodeling rather than modeling (rat), the increased resorption largely counteracts the increased bone formation. So far, 2MD has not been tested for reduction of fractures in this population. However, its selectivity includes the parathyroid gland. Thus in the 5/6-nephrectomy model of chronic renal failure, 2MD is much more potent than currently available vitamin D compounds used to suppress secondary hyperparathyroidism of renal failure without causing hypercalcemia. It is currently in phase 2B trials in patients on dialysis.

The effects of different intensities of exercise and active vitamin D on mouse bone mass and bone strength

“…Calcitriol also showed a modest inhibition on bone resorption (Fig. 5a, b), as previously reported [18][19][20]. In the presence of calcitriol, the medium level of exercise, but △ p < 0.05, △△ p < 0.01 when compared to high-intensity group not the low or high level, further reduced the osteoclast surface (Fig.…”

“…Active vitamin D has been shown to improve bone health in the young and the old [13][14][15][16][17], and its derivatives have been approved to treat osteoporosis in some countries. Although the main function of natural vitamin D ingested from the diet, after being converted to the active form, is to increase intestinal absorption and kidney resorption of calcium, pharmacological doses of active vitamin D have been shown to increase bone mass and density, mainly by inhibiting osteoclastogenesis and bone resorption [18][19][20]. An alternative therapy is physical exercise.…”

Hydrosulfonylation Reaction with Arenesulfonyl Chlorides and Tetrahydrofuran: Conversion of Terminal Alkynes into Cyclopentylmethyl Sulfones

“…Moreover, several biologically active compounds containing a sulfone functional group are known . Sulfones are also useful building blocks, as illustrated by the preparation of 26,28‐methylene‐1‐α,25‐dihydroxyvitamin D2, a drug candidate for the treatment of osteoporosis, on the basis of a Julia olefination process involving a homochiral phenyl cyclopentylmethyl sulfone (Scheme ). The addition of sulfonyl radicals to alkenes is one of the mildest methods to introduce a sulfonyl group into a molecule.…”

Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets

“…12,14 There is no doubt that vitamin D has important actions on bone and parathyroid cells, 5 as discussed in many chapters in special issue. [78][79][80] However, these actions can apparently be compensated for in vivo if the calcium level is normalized. That high doses of oral calcium can improve hypocalcemia in children with HVDRR suggests that VDR-independent pathways of calcium absorption must come into play in the absence of functional VDR.…”