Calcitriol derivatives

Calcitriol Derivatives with Heterocyclic Units in the Side-Chain... 

Since a synthetic route to heterocyclic calcitriol derivatives was still lacking, explorative research had to be carried out. The vitamin D aldehyde 1 was prepared according to the Leo protocol [192] followed by a photosensitized isomerization of the triene unit in seven steps (Scheme 10.2). Wittig-Horner olefination selectively yielded the E-double bond configuration of the Weinreb amide 2. Reduction with diisobutylaluminum hydride gave the unsaturated aldehyde 3 without any evidence for overreduction. This aldehyde could serve as a valuable intermediate for further elaboration of the side-chain [194],... 

The biological effects of these novel oxazole calcitriol derivatives have been assessed at Schering. Initially it turned out that the 24-0 H stereochemistry is crucial for biological activity. As the 24a-OH analogs were only very weakly active (data not shown), their respective 24(1-014 counterparts exerted substantial activity in all systems investigated. 

The immunomodulatory activity of calcitriol derivatives can be investigated in PBMCs, giving hints for the application of such compounds in the treatment of immune disorders. All oxazole calcitriols possessing the 24(3-OH situation showed strong agonistic potency in this cell system. Overall, the butyl compound 28b was detected as the most potent analog in this assay, almost reaching the potency level of calcitriol. 

Vitamin A (retinol), present in carnivorous diets, and the provitamin (P-carotene), found in plants, form retinaldehyde, utilized in vision, and retinoic acid, which acts in the control of gene expression. Vitamin D is a steroid prohormone yielding the active hormone derivative calcitriol, which regulates calcium and phosphate metaboUsm. Vitamin D deficiency leads to rickets and osteomalacia. 

Calcitriol and tacalcitol are other vitamin D derivatives that have been studied for treatment of psoriasis. 

Calcitriol must be protected from air and light. The drug substance exhibits good stability when stored at -15°C to -25°C in an argon atmosphere. The material is stable at room temperature when dissolved in a vegetable oil derivative, containing antioxidants, such as is used in calcitriol soft gelatin capsules (19). 

Halket and Lisboa (25) examined several Vitamin D derivatives by capillary gas chromatography coupled with mass spectrometry. This technique offered the advantages of great sensitivity and separating power. Retention times and fragmentation patterns for ergocalciferol, cholecalciferol and calcitriol were reported. 

Calcitriol is a derivative of vitamin D (see p. 364). On exposure to ultraviolet light, a precursor of the hormone can also arise in the skin. Calcitriol itself is synthesized in the kidneys (see p. 330). Calcitriol promotes the resorption of calcium in the intestine and increases the Ca "" level in the blood. 

Calcipotriol is a vitamin D3 derivative which is used as a topical agent in the treatment of psoriasis. Although not completely elucidated its mechanism of action seems to be based on inhibition of the proliferation and stimulation of the differentiation of epidermal keratinocytes. Adverse effects include irritation of the skin but also urticarial reactions. Calcipotriol has 100 fold less vitamin D activity as its active vitamin D3 metabolite calcitriol. However, calcipotriol in overdose can cause symptoms of hypercalcemia. 

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible. 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metabolically active vitamin D hormone results from two successive hydroxylations in the liver at position 25 (- calcifediol) and in the kidney at position 1 (- calcitriol = vitamin D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca2+ and phosphate. Vitamin D hormone promotes enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vitamin D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vitamin D is given in liver disease, calcifediol may be indi-... 

The discovery that vitamin D3 (1), also called calciol [I], is actually a pro-hormone and not a vitamin as previously assumed has induced intense worldwide research activities within the last 20 years. Nowadays, it is known that the prohormone is transformed in liver and kidney into physiologically much more active metabolites by hydroxylation. In particular, the la,25-dihy-droxylated derivative, calcitriol (3), performs a key function in the regulation of different physiological events [2]. Some hydroxylated vitamin D derivatives and structural analogs are currently being clinically tested as drugs for the treatment of a range of human diseases such as cancer, psoriasis or immune defects. 

Most vitamin D is excreted in the bile less than 5% is excreted as water-soluble metabolites in urine. Some 2% to 3% of the vitamin D in bUe is cholecalciferol, calcidiol, and calcitriol, but most is a variety of polar metabolites and their glucuronide conjugates. In most tissues, the major pathway for inactivation of calcitriol is by way of 24-hydroxylation to calcitetrol, then onward oxidation byway of the 24-oxo-derivative, 23-hydroxylation, and oxidation to calcitroic acid (see Figure 3.3). In addition, a variety of hydroxylated and other polar metabolites have been identified in bile, and many of these onward oxidation products also undergo glucuronide conjugation in the liver (Reddy and Tserng, 1989). 

Vitamin E is the common name for o-a-tocopherol and is an oily liquid at room temperature and is also an antioxidant. Alfacalcidol, a dehydroxy derivative of calcitriol, is formulated as a solution in a mixture of sesame oil and a-tocopherol in 0.25 pg, 0.5 pg, and 1.0 pg One-Alpha soft gelatin capsules. Ethyl icosapen-tate is used in the treatment of hyperlipidemia and arteriosclerosis obliterans, and exists as a liquid at ambient room temperature that is formulated as a solution in a-tocopherol in 300 mg Epadel soft gelatin capsules. 

Ergocalciferol is derived from ergosterol in the diet. Colecalciferol is derived from endogenous cholesterol. Both are also synthesized in the skin. Colecalciferol and ergocalciferol are converted in the liver by hydroxylation to calcifediol, which is weakly active. Calcifediol is activated in the kidneys by further hydroxylation to alfacalcidol, which is highly active, and calcitriol, which is weakly active. Calcitriol is deactivated by further hydroxylation in the kidney to 1 a,24,25-trihydroxycolecalcif erol. 

Bones are constantly dissolved by osteoclasts and remineralized by osteoblasts in response to mechanical forces. Osteoclasts possess an acidic compartment and pass demineralized bone products to the periosteum (Sect. 1). They develop in stress-induced bony microcracks and are activated by differentiation factors secreted by osteoblasts, especially after menopause. Menopausal osteoporosis is controlled by drugs that are a stable form of pyrophosphate (bisphosphonate) or cathepsin K inhibitors (Sect. 2). The calcium ion concentration of blood is raised by parathyroid hormone and a vitamin D derivative called calcitriol. Parathyroid hormone causes kidneys to excrete phosphate, retain calcium, and activate calcitriol production (Sect. 3). Calcitriol induces calcium transporter proteins in osteoclasts and intestinal epithelium, where they move calcium from bone or diet into blood (Sect. 4). The chapter concludes with a discussion of calcitonin which lowers blood calcium concentrations by reversing parathyroid hormone effects on the kidney and inhibiting osteoclast activity (Sect. 5). 

Vitamin D is a fat soluble vitamin derived from cholesterol. In the human epidermis (skin), sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol (Fig. 10.10a). The 7-dehydrocholesterol leaks into the blood where it isomerizes to cholecalciferol (vitamin D3, Fig. 10.10b and c). Cholecalciferol is enzymatically hydroxylated at C25 in the liver (25-cholecalciferol) and then passes to the kidney where another enzyme is activated by parathyroid hormone to hydroxylate it at Cl, forming calcitriol (Fig. lO.lOd). The kidney hydroxylase is sensitive to feedback inhibition. As the amount of calcitriol increases, it binds to the hydroxylase and alters the specificity of the kidney enzyme. Additional 25-cholecal-ciferol is hydroxylated to 24,25-dihydroxycholecalciferol (inactive calcitriol) instead of 1,25 dihydroxycholecalciferol (calcitriol). Other vitamin D derivatives that can be converted to calcitriol are obtained enzymatically from cholesterol in other vertebrates. The most common of these are vitamin D3 (lamisterol) and D2 (ergosterol) from cold-water fish such as cod, where their presence keeps membranes fluid at low body temperatures 10-20°C. 

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