VDR/vitamin D receptor.
Impurity F of Calcipotriol targets the vitamin D receptor (VDR)-like receptors, similar to its parent compound Calcipotriol. VDR is a nuclear receptor that regulates gene transcription involved in cell proliferation, differentiation, and calcium homeostasis.

Calcipotriol is a novel vitamin D3 analogue developed for topical treatment of psoriasis. Calcipotriol is believed to act via regulation of cell proliferation and differentiation. In this respect calcipotriol is as potent as 1 alpha, 25(OH)2D3, the physiologically active form of vitamin D3, but its calcaemic activity in vivo is 100 to 200 times lower. In the present investigation, the effects of calcipotriol on cell growth regulation in vitro and on calcium metabolism in vivo were compared to those exerted by a number of metabolites and analogues of vitamin D3. Besides 1 alpha, 25(OH)2D3, these included the two physiologically occurring metabolites 25(OH)D3 and 24,25(OH)2D3, and the two synthetic analogues 1 alpha (OH)D3 and 1 alpha, 24(OH)2D3. 25(OH)D3 and 24,25(OH)2D3 were shown to be inactive both in vitro and in vivo. 1 alpha (OH)D3 was found to have a low biological activity in vitro, but was highly calcaemic in vivo after biotransformation to 1 alpha, 25(OH)2D3. Calcipotriol, 1 alpha, 24(OH)2D3 and 1 alpha, 25(OH)2D3 were all three potent regulators of cell proliferation and differentiation in vitro. In vivo, only calcipotriol showed a greatly reduced calcaemic activity after both oral and intravenous administration. It is concluded that calcipotriol, with a reduced risk of inducing calcaemic side-effects upon absorption from the skin, possesses a favourable therapeutic profile for topical treatment of hyperproliferative diseases[1].

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As an impurity and synthetic intermediate, Impurity F of Calcipotriol itself is not typically evaluated for intrinsic in vitro pharmacological activity. Calcipotriol, the parent drug, exhibits antiproliferative activity against human cancer cell lines including HL-60, MCF-7, T47D, and SCC-25.

In vivo activity data for Impurity F of Calcipotriol are not applicable, as this compound is an intermediate and impurity standard rather than a therapeutic agent. It is not administered to animals for pharmacological evaluation. Its relevance lies in the synthesis and analytical characterization of Calcipotriol.

In vitro enzyme/receptor binding assays for Impurity F of Calcipotriol are not performed as it is not a pharmacologically active compound. It serves as a chemical reference or intermediate for the synthesis of Calcipotriol. VDR binding assays are conducted on the parent drug for quality control purposes.

Cell-based assays for Impurity F of Calcipotriol are not applicable. As a chemical intermediate and impurity, it is used in organic synthesis and analytical chemistry rather than cell-based biological studies. Its presence is monitored during the manufacturing process of Calcipotriol.

In vivo animal protocols for Impurity F of Calcipotriol are not applicable. The compound is a chemical intermediate used in the synthesis of Calcipotriol and as a reference standard for impurity profiling in pharmaceutical quality control.

Pharmacokinetic properties of Impurity F of Calcipotriol have not been characterized. The compound has a molecular weight of 641.13 and formula C39H68O3Si2. It is unstable in solution and should be stored at -20degC, protected from light, and under nitrogen.

Toxicological data for Impurity F of Calcipotriol are not available, as the compound is not intended for human or animal administration. It is a research-grade chemical intermediate and impurity standard used in controlled laboratory settings. Standard safety precautions should be followed.

[1]. Binderup (1993) Comparison of calcipotriol with selected metabolites and analogues of vitamin D3: effects on cell growth regulation in vitro and calcium metabolism in vivo. Pharmacol.Toxicol. 72 240.

[2]. Knutson et al (1997) Pharmacokinetics and systemic effect on calcium homeostasis of 1a,24-dihydroxyvitamin D2 in rats. Biochem.Pharmacol. 53 829.

[3]. Wietrzyk et al (2007) Antitumor properties of diastereomeric and geometric analogs of vitamin D3. Anticancer Drugs 18 447.111.

[4]. Lise Binderup,, Erik Bramm. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochemical Pharmacology. Volume 37, Issue 5, 1 March 1988, Pages 889-895.

1α,24-Dihydroxyvitamin D2 (1α,24(OH)2D2) is a metabolite of 1α-hydroxyvitamin D2 (1α-OH-D2), a prodrug under development for the treatment of secondary hyperparathyroidism in end-stage renal disease. This prodrug has a wider therapeutic index than its corresponding vitamin D3 analogue, likely because at high doses, the hepatic metabolic pathway of 1α-OH-D2 is converted from 1α,25-dihydroxyvitamin D2 (1α,25(OH)2D2) to 1α,24(OH)2D2. This report describes the pharmacokinetics of 1α,24(OH)2D2 in rats and its systemic effects on serum and urinary calcium. These properties are compared with 1α,25(OH)₂D₂, calcitriol (the active metabolite of endogenous vitamin D₃), and calcipotriol, a vitamin D analogue known for its rapid clearance and minimal impact on calcium homeostasis. A comparison of blood concentration curves from zero to infinity shows that the systemic exposure of 1α,24(OH)₂D₂ is approximately one-fifth that of 1α,25(OH)₂D₂ or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailability and circulating half-life of 1α,24(OH)₂D₂ and calcitriol are similar, while those of calcipotriol are much lower. In vitamin D-deficient rats, oral administration of both 1α,25(OH)₂D₂ and calcitriol induced a dose-dependent increase in serum calcium levels, while a similar response was achieved with oral administration of 1α,24(OH)₂D₂ at a dose 30 times higher. Dose-response curves plotted after oral and subcutaneous injection of 1α,24(OH)₂D₂, calcitriol and calcipotriol in normal rats showed that 1α,24(OH)₂D₂ increased serum and urinary calcium levels to a much lesser extent than calcitriol, but slightly more than calcipotriol. These properties of 1α,24(OH)₂D₂ suggest that the formation of this metabolite from 1α-OH-D₂ helps reduce the toxicity of 1α-OH-D₂ and suggests that 1α,24(OH)₂D₂ itself has therapeutic potential. [2]

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1,25-dihydroxyvitamin D3 analogues with an inverted configuration at C-1 or C-24 in the side chain and an E or Z double bond at C-22 or C-5 in the triene system were studied in vitro for their antiproliferative activity against a variety of human cancer cell lines. Analogs coded PRI-2201 (calcipotriol), PRI-2202, and PRI-2205, as well as calcipotriol and tacalcitol (used as control drugs), showed antiproliferative activity against human HL-60, HL-60/MX2, MCF-7, T47D, SCC-25, and mouse WEHI-3 cancer cell lines. In vivo toxicity studies showed that PRI-2202 and PRI-2205 were less toxic than the control drugs. No changes in body weight were observed even after administration at a total dose of 2.5–5.0 mg/kg over 5 consecutive days. Calcipotriol and tacalcitol showed toxicity at doses 100 times lower than the control drugs under the same dosing regimen. Calcipotriol was lethal to all mice after administration of a total dose of 5.0 mg/kg. Compared to calcipotriol, calcipotriol, or PRI-2202, the analog PRI-2205 appeared to be more effective in inhibiting the growth of Levis lung cancer tumors in mice. This analogue did not show calcification activity at doses that inhibited tumor growth in vivo, nor at higher doses. [3]

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Impurity F of Calcipotriol is a chemical intermediate and impurity standard used in the synthesis and analytical testing of Calcipotriol (Calcipotriene), a vitamin D3 analog indicated for the topical treatment of plaque psoriasis. Calcipotriol was first approved in Europe in 1991 and is marketed in over 80 countries. This compound is for research and analytical use only, not for human therapeutic application.

C39H68O3SI2

641.12642

640.471

112875-61-3

Calcipotriol;112965-21-6

13917667

White to off-white solid powder

11.149

1

3

11

44

1130

7

C[C@H](/C=C/[C@H](C1CC1)O)[C@H]2CC[C@@H]\3[C@@]2(CCC/C3=C\C=C\4/C[C@H](C[C@@H](C4=C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C

DIMYHZDULFSWLS-YFSXTQNDSA-N

InChI=1S/C39H68O3Si2/c1-27(16-23-35(40)30-18-19-30)33-21-22-34-29(15-14-24-39(33,34)9)17-20-31-25-32(41-43(10,11)37(3,4)5)26-36(28(31)2)42-44(12,13)38(6,7)8/h16-17,20,23,27,30,32-36,40H,2,14-15,18-19,21-22,24-26H2,1,3-13H3/b23-16+,29-17+,31-20+/t27-,32-,33-,34+,35-,36+,39-/m1/s1

(E,1S,4R)-4-[(1R,3aS,4E,7aR)-4-[(2E)-2-[(3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-1-cyclopropylpent-2-en-1-ol

Impurity F of Calcipotriol; Calcipotriol Impurity F; Impurity of Calcipotriol; 4SP93VP62P; (5Z,7E,22E,24S)-24-Cyclopropyl-1alpha,3beta-bis(((1,1-dimethylethyl)dimethylsilyl)oxy)-9,10-secochola-5,7,10(19),22-tetraen-24-ol; (E,1S,4R)-4-[(1R,3aS,4E,7aR)-4-[(2Z)-2-[(3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-1-cyclopropylpent-2-en-1-ol; UNII-4SP93VP62P;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.  (3). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~38.99 mM)

Solubility in Formulation 1: ≥ 1.25 mg/mL (1.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.25 mg/mL (1.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)