Methyl substitution of the 25-hydroxy group on 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 (2MD) reduces potency but allows bone selectivity

Grzywacz, Pawel; Plum, Lori A.; Siciński, Rafał R.; Clagett‐Dame, Margaret; DeLuca, Hector F.

doi:10.1016/j.abb.2006.09.028

Cited by 19 publications

(39 citation statements)

References 22 publications

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“…Since the hydroxy compound 11 was previously obtained in our laboratory, by degradation of the commercial vitamin D 2 16 followed by reconstruction of the side chain, 19 we focused our efforts on the preparation of its 21-nor analog 12 (steroidal numbering). As a starting compound, we have chosen methylketone 17 (Scheme 1) prepared from vitamin D 2 16 as described by Posner.…”

Section: Resultsmentioning

confidence: 99%

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

Barycki

Siciński

Plum

et al. 2009

Bioorganic & Medicinal Chemistry

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The 18-nor (7), 21-nor (8) and 18,21-dinor (9) analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (6, 2MD) were prepared by convergent syntheses. The known phosphine oxide 10 was coupled by the Wittig–Horner process with the corresponding C,D-fragments (13–15), obtained by a multi-step procedure from commercial vitamin D2. The goal of our studies was to examine the influence of removal of the methyl groups located at carbons 13 and 20 on the biological potency of 2MD in the hope of finding analogs with improved therapeutic profiles. Replacement of the 20-methyl with hydrogen in 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) did not affect binding to the rat vitamin D receptor and had little effect on transcription activity and on HL-60 differentiation. However, the mobilization of calcium from bone was largely eliminated while intestinal calcium transport remained strong. Curiously, removal of both the C-13-methyl and 20-methyl restored slightly the bone calcium mobilizing activity. Thus, the 21-nor analog of 2MD may provide a potent analog with a greater margin of safety than 2MD.

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Section: Resultsmentioning

confidence: 99%

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

Barycki

Siciński

Plum

et al. 2009

Bioorganic & Medicinal Chemistry

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“…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).…”

Section: Present Use Of Vdras In Patients With Ckdmentioning

confidence: 99%

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

Valdivielso

Cannata-Andía

Coll

et al. 2009

American Journal of Physiology-Renal Physiology

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Valdivielso JM, Cannata-Andía J, Coll B, Fernández E. A new role for vitamin D receptor activation in chronic kidney disease. Am J Physiol Renal Physiol 297: F1502-F1509, 2009. First published July 22, 2009 doi:10.1152/ajprenal.00130.2009.-Vitamin D has proven to be much more than a simple "calcium hormone." The fact that the vitamin D receptor has been found in cells not related to mineral metabolism supports that statement. The interest of nephrologists in vitamin D and its effects beyond mineral metabolism has increased over the last few years, evidencing the importance of this so-called "sunshine hormone." In the present review, we highlight the most recent developments in the traditional use of vitamin D in chronic kidney disease (CKD) patients, namely, the control of secondary hyperparathyroidism (sHPT). Furthermore, we also explore the data available regarding the new possible therapeutic uses of vitamin D for the treatment of other complications present in CKD patients, such as vascular calcification, left ventricular hypertrophy, or proteinuria. Finally, some still scarce but very promising data regarding a possible role of vitamin D in kidney transplant patients also are reviewed. The available data point to a potential beneficial effect of vitamin D in CKD patients beyond the control of mineral metabolism.VITAMIN D IS A STEROID HORMONE that has long been known for its important role in regulating body levels of calcium (Ca) and phosphorus (P) and in mineralization of bone. However, there is an increasing amount of data proving that vitamin D exerts its effects beyond kidney, intestine, and bone (Fig. 1). The active form of vitamin D (calcitriol) mediates its biological effects by binding to the vitamin D receptor (VDR), which then translocates to the nuclei of target cells (for review, see Ref. 47). The VDR is a ligand-activated transcription factor that, after activation, recruits cofactor molecules and binds to specific DNA binding sites to modify the expression of target genes. Ligand-mediated conformational changes of the VDR contribute to specific mechanisms in its signaling cascade. Thus the structural chemical modification of active vitamin D is a powerful tool in discovering new compounds that show selective activation of the VDR. Over the last years, a number of new VDR activators (VDRAs), defined as compounds that can bind to VDR and induce its activation, have been synthesized and used in several diseases, including in patients with CKD. Their potential as new therapeutic agents has boosted this area of research. Moreover, new evidence suggests that VDR polymorphisms may influence the response to VDRAs (125). Present Use of VDRAs in Patients with CKDOne of the main complications in patients with CKD is the development of secondary hyperparathyroidism (sHPT). In the past, the increase in parathyroid gland (PTG) size and parathyroid hormone (PTH) synthesis were attributed to a decrease in circulating Ca. As a result, patients with sHPT were treated with oral vitamin D metabolites to correct ...

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“…The A-ring fragment 26 was prepared according to the published procedure [15] whereas the syntheses of the necessary Δ 22 E -25-hydroxy C,D-ring ketones ( 20 – 21 ; 24a,b – 25a,b ) are presented in Scheme 1. As recently reported by us [14], the Wittig reaction between the C,D-ring aldehydes 10 and 11 , previously prepared in our laboratory from commercial vitamin D 2 [19], and either the hydroxyphosphonium bromide 12 [20] or the hydroxyphosphonium iodides 15a and 15b , easily prepared in our laboratory from commercially available ( S )- and ( R )-1,3-butanediols [14,20], efficiently provided only the olefinic products with the E -geometry of the introduced double bond 13 – 14 and 16a,b – 17a,b , respectively [14,20]. Then, after protection of the tertiary hydroxyl groups as tert -butyldimethylsilyl ethers 18 – 19 and 22a,b – 23a,b , the removal of the benzoyl group under basic conditions gave the secondary alcohols, which were immediately subjected to oxidation with PDC affording the Grundmann ketones 20 – 21 and 24a,b – 25a,b in very good yields.…”

Section: Resultsmentioning

confidence: 99%

26-Desmethyl-2-methylene-22-ene-19-nor-1α,25-dihydroxyvitamin D3 compounds selectively active on intestine

et al. 2014

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Six new analogs of 2-methylene-19-nor-1α,25-dihydroxyvitamin D3, 6–7 and 8a,b–9a,b, have been synthesized. All compounds are characterized by a trans double bond located in the side chain between C-22 and C-23. While compounds 6 and 7 possess C-26 and C-27 methyls, compounds 8a,b and 9a,b lack one of these groups. A Lythgoe-based synthesis, employing the Wittig–Horner reaction was used for these preparations. Two different types of Δ22E-25-hydroxy Grundmann’s ketone, having either only one stereogenic center located at position C-20 (20 and 21), or two stereogenic centers located at 20- and 25-positions (24a,b–25a,b) were obtained by a multi-step procedure from commercial vitamin D2. The introduction of a double bond at C-22 appeared to lower biological activity in vitro and in vivo. Further removal of a 26-methyl in these analogs had little effect on receptor binding, HL-60 differentiation and CYP24A expression but markedly diminished or eliminated in vivo activity on bone calcium mobilization while retaining activity on intestinal calcium transport.

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Methyl substitution of the 25-hydroxy group on 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 (2MD) reduces potency but allows bone selectivity

Cited by 19 publications

References 22 publications

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

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

26-Desmethyl-2-methylene-22-ene-19-nor-1α,25-dihydroxyvitamin D3 compounds selectively active on intestine

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