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Cyclic ether vitamin D3 compounds, 1alpha(OH)3-epi-vitamin D3 compounds and uses thereof

a technology of cyclic ether and vitamin d3, which is applied in the field of cyclic ether vitamin d3 compounds, 1alpha (oh) 3epivitamin d3 compounds, can solve the problems of limited clinical applications of vitamin d/sub>3 and its structural analogs, and achieves enhanced stability, reduced growth or activity of cells, and improved biological properties

Inactive Publication Date: 2008-08-07
WOMEN & INFANTS HOSPITAL OF RHODE ISLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]In a preferred embodiment, the vitamin D3 compound of formulas I and II used in the treatment has improved biological properties compared to vitamin D3, such as enhanced stability and / or reduced toxicity.
[0020]In yet another aspect, the present invention provides a method of preventing or protecting against neuronal loss by contacting a vitamin D3-responsive cell, e.g., a neuronal cell, with a vitamin D3 compound of formulas I and II to prevent or retard neuron loss.

Problems solved by technology

However, clinical applications of vitamin D3 and its structural analogs have been limited by the undesired side effects elicited by these compounds after administration to a subject, such as the deregulation of calcium and phosphorous homeostasis in vivo that results in hypercalcemia.

Method used

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  • Cyclic ether vitamin D3 compounds, 1alpha(OH)3-epi-vitamin D3 compounds and uses thereof
  • Cyclic ether vitamin D3 compounds, 1alpha(OH)3-epi-vitamin D3 compounds and uses thereof
  • Cyclic ether vitamin D3 compounds, 1alpha(OH)3-epi-vitamin D3 compounds and uses thereof

Examples

Experimental program
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example 1

Isolation and Identification of a Cyclic Ether Metabolite of 1α,25-dihydroxy-Vitamin D3 in Human Keratinocytes

[0180]As described herein, 1α25(OH)2-3-epi-D3 is metabolized into a less polar metabolite than 1α25(OH)2-3-epi-D3, peak M1, in human keratinocytes (FIG. 2). FIG. 2 shows the HPLC profile and UV spectra of the metabolites produced in human keratinocytes incubated with 1α25(OH)2-3-epi3D3 (1 uM) for 24H. On a straight phase HPLC system, this metabolite (M1) is more polar than 25(OH) D3 but less polar than 1α25(OH)2D3 and similar to that of 1α(OH)D3. Mass spectrometric analysis reveals a molecular ion of 414 m / z, which is 2 mass units less than the starting 1α25(OH)2D3, shown in FIG. 3. FIG. 3 shows the mass spectra of 1α(OH)2-3-epi-D3 (M) (upper panel) and its cyclic ether metabolite (M1) (lower panel) isolated from human keratinocytes incubated with 1α25(OH)2-3-epi-D3(1 uM) for 24 h. The typical fragments at m / z 134 and 152 m / z indicate an unmodified A-ring and cistriene struc...

example ii

Isolation and Identification of a 3-Epi Metabolite of 1α hydroxy-Vitamin D3 in Human Keratinocytes

[0182]FIG. 5A shows the metabolism of 1α(OH)-D3 into its 3 epi form in the osteosarcoma cell line UMR-106. Peak A represents the 3-epi form of 1α(OH)D3. Peak B corresponds to the substrate, 1α(OH)D3. The insert panels show the UV spectra of the various metabolites as monitored by photodiode array detector. FIG. 5B shows a schematic representation of the 3-epimerization of 1α(OH)D3 into 1α(OH)-3-epi vitamin D3. Similar to 1α(OH)D3, 1α(OH)-3-epi vitamin D3 can be converted into the 25-hydroxylated form in vivo.

[0183]1α(OH)D3 compounds are currently used in the treatment of osteoporosis. Thus, 3-epi forms of these compounds may be used as substitutes for 1α(OH)D3 compounds in treating osteoporosis.

example iii

Confirmation of 3-epi Configuration of 1α(OH) 3-epi Vitamin D3

[0184]To confirm the production of 1α(OH) 3-epi vitamin D3 in bone cells the metabolites of 1α-3-epi-D3 produced by the osteosarcoma cell line (UMR-106) were analyzed by mass spectroscopy. FIG. 6 shows the mass spectra of 1α(OH)D3 (upper panel) and its 3-epi metabolite (lower panel). A comparison of these two mass spectra revealed difference in peaks observed only in the 3-epi metabolite, for example, fragments having molecular weights of approximately m / z 57, 217, 312 and 529 (lower panel). The mass spectrum of the 3-epi metabolite was independently confirmed to be 1α(OH) 3-epi vitamin D3.

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Abstract

Novel cyclic ether vitamin D3 compounds having a cyclic ether side chain are disclosed. These compounds were first identified as metabolites of 3-epi vitamin D3 produced via a tissue-specific metabolic pathway which catalyzes the formation of a cyclic ether structure. Also disclosed are 1α(OH) 3-epi vitamin D3 compounds, which are produced via the epimerization of a 3-β-hydroxyl group of 1α(OH) vitamin D3 precursor in vivo. The vitamin D3 compounds of the present invention can be used as substitutes for natural and synthetic vitamin D3 compounds.

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. provisional application Application No. 60 / 046,690 filed on May 16, 1997, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The importance of the vitamin D in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified as a “vitamin” that was essential for the normal development of the skeleton and maintenance of calcium and phosphorous homeostasis.[0003]Studies involving the metabolism of vitamin D3 (cholecalciferol) were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin D3 [25(OH)2D3] (Blunt, J. W. et al. (1968) Biochemistry 6:3317-3322) and the hormonally active form, 1α, 25(OH)2D3 (Myrtle, J. F. et al. (1970) J. Biol. Chem. 245:119...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/351C07D309/06A61K31/047C07C33/14A61P3/00A61P19/10A61K31/045A61P3/02A61P3/14A61P5/18A61P17/00A61P19/08A61P43/00C07C401/00C07D303/14C07D307/33C07D309/04
CPCC07C401/00C07D303/14C07D309/06C07D309/04C07D307/33A61P17/00A61P19/08A61P19/10A61P3/00A61P3/02A61P3/14A61P43/00A61P5/18
Inventor REDDY, SATYANARAYANA G.
Owner WOMEN & INFANTS HOSPITAL OF RHODE ISLAND
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