Vitamin D analogs

Isomerization of double bonds in vitamin D analogs such as calciferol by oxidation and reduction has been carried out via the formation of the tt-allylpalladium complex 334 with PdCl2(PhCN)2 in 70% yield, followed by hydride reduction to afford 335[295],... 

CF patients with low bone mineral density and low serum vitamin D levels may improve bone health through supplemental vitamin D analogs beyond those found in standard CF vitamins. The optimal dose and analog have not been determined. For ergocalciferol, a minimum of 400 IU and 800 IU... 

Other vitamin D analogs available in the United States include paricalcitol (19-nor-l,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL) and doxercalciferol (1 -a-hydroxyvitamin D2, Hectoral by Bone Care International, Middleton, WI). Alfacalcidiol (1-a-hydroxyvitamin D3) is only available outside the United States. Paricalcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on... 

Calcipotriene (Dovonex) is a synthetic vitamin D analog used for mild to moderate plaque psoriasis. Improvement is usually seen within 2 weeks of treatment, and approximately 70% of patients demonstrate marked improvement after 8 weeks. Adverse effects occur in about 10% of patients and include lesional and perilesional burning and stinging. Calcipotriene 0.005% cream, ointment, or solution is applied one or two times a day (no more than 100 g/wk). 

Calcitriol (Rocaltrol, Calcnex) [Antihypocalcemic/Vitamin D Analog] Uses Reduction of i PTH levels, -iTca on dialysis Action 1,25-Dihydroxycholecalcifool (vit D analog) Dose Adul. Renal failure 0.25 mcg/d PO, t 0.25 mcg/d q4-6wk PRN 0.5 meg 3 x/wk IV, t PRN Hypoparathyroidism ... 

A. Ohno, M. Shimizu, S. Yamada, Fluorinated vitamin D analogs to probe the conformation of vitamin D in its receptor complex F-NMR studies and biological activity, Chem. Pharm. Bull. 50 (2002) 475-483. 

Vitamin D analog of choice for prevention and treatment of renal osteodystrophy less expensive than calcitriol... 

Contraindications Hypercalcemia, malabsorption syndrome, vitamin D toxicity, hypersensitivity to doxercalciferol or other vitamin D analogs... 

Because of the importance of osteoporosis, the area of vitamin D research has become exceptionally active in the generally quiescent vitamin field. Vitamin D analogs such as calcitriol (8.58, la,25,25-trihydroxycholecalciferol) and other compounds have been suggested as new drugs for these conditions. 

Doxercalciferol, the active ingredient in Hectorol, is a synthetic vitamin D analog that undergoes metabolic activation in vivo to form 1 (alpha),25-dihydroxyvitamin D2 (l(alpha),25-(OH)2D2), anaturally occurring, biologically active form of vitamin D2. Hectorol is available as soft... 

Vitamin D analogs Calcifediol (Calderol) Calcitriol (Rocaltrol) Dihydrotachysterol (DHT, Hytakerol) Ergocalciferol (Calciferol, Drisdol) Generally enhance bone formation by increasing the absorption and retention of calcium and phosphate in the body useful in treating disorders caused by vitamin D deficiency, including hypocalcemia, hypophosphatemia, rickets, and osteomalacia... 

Vitamin D is a precursor for a number of compounds that increase intestinal absorption and decrease renal excretion of calcium and phosphate. Metabolites of vitamin D and their pharmacologic analogs are typically used to increase blood calcium and phosphate levels and to enhance bone mineralization in conditions such as osteodystrophy, rickets, or other situations where people lack adequate amounts of vitamin D. Vitamin D analogs such as calcitriol have also been combined with calcium supplements to help treat postmenopausal osteoporosis,4,9 and to treat bone loss caused by antiinflammatory steroids (glucocorticoids see Chapter 29 28.76 Specific vitamin D-related compounds and their clinical applications are listed in Table 31-5. 

Elimination reaction occurs under acidic conditions for the API vitamin D analog to yield the corresponding major degradation products, E/Z isomers (Fig. 80) (121). 

Figure 80 Vitamin D analog degradation under aqueous conditions leads to elimination of the tertiary alcohol.

For dermatological treatment the main focus has been on vitamins A and D. Retinoids have been used systemically and topically for the treatment of acne and a variety of hyperkeratotic disorders including psoriasis, ichthyoses, and lichenoid dermatoses as well as skin cancer.1 Vitamin D-analogs are of great importance for the topical treatment in psoriasis. 

Topical vitamin D analogs as calcipotriol, and tacalcitol are well established, effective and safe preparations for the treatment of psoriasis vulgaris due to their antiproliferative and prodifferentiating effects on keratinocytes.110 They can be used either as monotherapy or in combination with other treatment modalities.111 The main side effect is the increasing risk ofhypercalcaemia with increasing amounts of vitamin D analogs applied to the skin. 

Vitamin D analogs seem to be limited in dermatology to the topical treatment of psoriasis vulgaris, which is not least because of their overall effects on calcium and phosphorus homoostasis. 

The examples discussed in this paper demonstrate that Pd-catalyzed coupling reactions can be successfully utilized in the convergent (modular) synthesis of vitamin D-active compounds. The new synthetic routes open an efficient and highly selective access to a variety of vitamin D analogs. While reliable methods exist today for the construction of the triene system and for the synthesis of the ring A precursors, the search for efficient total synthetic approaches to the CD building blocks still remain a challenging task for the future. 

In their role as enantioselective catalysts for the reduction of prochiral ketones, chiral oxazaborolidines have been used for the preparation of prostaglandins, PAF antagonists, a key intermediate of ginkgolide B, bilobalide, a key intermediate of forskolin, (/ )- and (S)-fluoxetine, (R)- and (S)-isopreterenol, vitamin D analogs, the carbonic anhydrase inhibitor the dopamine D1 agonist A-77636, ... 

An early example having potential commercial importance comes from tlie Trost laboratory s synthesis of vitamin D analogs (Scheme 6-23) [51], Their combination of vinyl bromide 129 and alkyne 130 to form triene 131 led to a concise and efficient synthesis of (-i-)-alphacalcidiol (134). In this reaction, vinyl bromide 129 participates in a bimolecular Heck reaction with alkyne 130 and the resulting alkenylpalladium intermediate 133 undergoes subsequent intramolecular Heck reaction with the pendant terminal alkene to provide 131. Under the reaction conditions, some of the desired product undergoes a [1,7]-hydrogen shift to yield 132. After thermal recycling of the minor component, a remarkable 76% yield of 131 was obtained. 

Several synthetic vitamin D analogs have been prepared and their activities investigated. Of particular importance for potential anti-cancer and immune supression drugs, are vitamin D compounds whose bone calcium activity is low and cell differentiation activity is high. Compound 1 and 2 are traditional vitamin D structures with high bone calcemic activity (calcium homeostasis) and only modest cell differentiation activity. 

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