Biologically active noncalcemic analogs of 1α,25-dihydroxyvitamin D with an abbreviated side chain containing no hydroxyl

Abstract

Since the discovery of the active metabolite of vitamin D, i.e., 1␣,25-dihydroxyvitamin D3, there has been a continuous effort to synthesize analogs able to carry out many of the functions of the native hormone without raising serum calcium concentration. The present report provides a series of previously undescribed analogs wherein this goal is realized. We have prepared 2-methylene-19-nor-1␣-hydroxyvitamin D analogs of 1,25-(OH)2D3 that possess only two to four carbons of the side chain without a hydroxyl thereon. Compared to 1,25-(OH)2D3, these analogs are slightly less active in binding to the vitamin D receptor, in causing HL-60 differentiation, and are slightly less active in in vitro transcription assays using the 24-hydroxylase promoter attached to a luciferase reporter gene. Of considerable importance is that these analogs, given to rats at daily doses of up to 70 g͞kg of body weight per day, are either unable or only slightly able to raise serum calcium concentration but are nevertheless able to suppress parathyroid hormone levels in plasma up to 100% and induce 24-hydroxylase mRNA in skin. Because of their ability to act in vivo without raising serum calcium levels, they may be of considerable interest for the systemic treatment of diseases such as psoriasis, cancer, and secondary hyperparathyroidism of renal failure, where a rise in serum calcium is undesirable.S ince the discovery that vitamin D must be metabolized to its biologically active form, 1␣,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], before it can function, an intense synthetic effort has been placed on preparing analogs of the vitamin D hormone with the hope that these analogs may be selective in their activity and might be useful in treating specific disorders (1). Most notable among new analogs are 19-nor-1,25-dihydroxyvitamin D 2 (Zemplar, Abbott) (2), 22-oxa-1␣,25-dihydroxyvitamin D 2 (3), MC-903 (calcipotriol) (4), 16-ene-23-yne-1␣,25-dihydroxyvitamin D 3 (5), and 24-difluoro-26,27-dimethyl-16-ene-1␣,25-dihydroxyvitamin D 3 (6). Calcipotriol has been successfully applied in topical treatment of psoriasis under the trade name of Dovonex (7), whereas the 22-oxa-1␣,25-(OH) 2 D 3 has been applied to renal osteodystrophy and psoriasis (3). These two compounds appear to be noncalcemic in their activity, primarily because they are rapidly metabolized and excreted (8, 9). Nevertheless, they have been quite useful in that their metabolic lability renders them considerably safer than the native hormone. Other analogs are also known to be metabolized rapidly (8, 9). The 19-nor-1␣,25-dihydroxyvitamin D 2 that is successfully marketed for renal osteodystrophy is also less calcemic but not because of rapid metabolism (10). Thus, the search continues for a vitamin D compound that remains in the circulation but is not effective in raising serum calcium, while still retaining noncalcemic activities. This paper reports a series of analogs that are clearly noncalcemic but are nevertheless systemically active. Materials and MethodsCompounds. Structures ...

A new role for vitamin D receptor activation in chronic kidney disease

“…Therefore, chemical modifications of the calcitriol molecule can result in selective VDRAs with a high degree of cell-tissue specificity. Two new compounds, 2-methylene-19-nor-(20S)-1␣-hydroxybishomopregnacalciferol (2MbisP) and its 20R isomer (2MbisP-20R) have been shown to be highly specific for lowering PTH, with almost no effect on Ca and P, whether released from bone or absorbed from the gut (91,114). In addition, other compounds, such as 2-methylene-19-nor-(20S)-1␣,25(OH) 2 D 3 (2MD) and 2␣-methyl-19-nor-(20S)-1␣,25(OH) 2 D 3 (2AMD) have a preference for bone, where they act to increase ostoclastogenesis and bone formation (41,55,99,103,104,108).…”

Kinetic Studies of 25-Hydroxy-19-nor-vitamin D3and 1α,25-Dihydroxy-19-nor-vitamin D3Hydroxylation by CYP27B1 and CYP24A1

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ABSTRACT:Our previous study demonstrated that 25 , 1993;Llach et al, 1998;Plum et al, 2004).Since the discovery of 1␣-hydroxylase in prostate cells in 1998, several groups have demonstrated that 25(OH)D 3 has the ability to inhibit cell proliferation in cultured prostate cells and concluded that 25(OH)D 3 was converted to 1␣,25(OH) 2 D 3 by prostatic CYP27B1 in an autocrine fashion before exerting antiproliferative activity (Barreto et al,

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“…However, because systemic administration of 1␣,25(OH) 2 D 3 can cause hypercalcemia and hypercalciuria, it is not suitable as a therapeutic agent for cancer treatment. Consequently, several laboratories have attempted to synthesize analogs of 1␣,25(OH) 2 D 3 with less or noncalcemic property (Abe-Hashimoto et al, 1993;Llach et al, 1998;Plum et al, 2004).…”

Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity

“…This compound when studied in vitro is able to bind to the receptor, albeit at a one-half log higher concentration. It stimulates transcription of a VDR-reporter gene system as well as in vitro differentiation and suppression of proliferation of HL-60 cells [9]. However, when tested in vivo in vitamin-D-deficient rats, this compound appears to have virtually no activity on intestine and bone calcium mobilization at doses where the vitamin D hormone is clearly active [9].…”