SYNTHESIS AND EVALUATION OF 1,25-(OH)2-D3 GLYCOSIDES

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1,25-Dihydroxyvitamin D3 and its analogs have proven to be useful as pharmacologic agents for a variety of diseases. 1,25-Dihydroxyvitamin D3 has been shown to be effective in maintaining bone mineral density and decreasing fracture rate in elderly women who suffer from osteoporosis and take this drug. However, this drug has not gained wide acceptance world wide because of its great potential of causing calcium toxicity including hypercalciuria, hypercalcemia, kidney stones and soft tissue calcification. Part of the reason for this concern, is that 1,25(OH)2D3 is the biologically active form of vitamin D and when given orally has a direct action on the small intestine by increasing the efficiency of calcium absorption. 1,25(OH)2D3 has also been demonstrated to be extremely effective both orally and topically for the treatment of psoriasis. However, since 1,25(OH)2D3 is a lipid soluble compound, its topical formulation is difficult and often requires an ointment based preparation. Greasy ointment preparations are less acceptable to patients than cream based ones. 1,25(OH)2D,3, when given orally, interacts directly with the small intestine to raise the efficiency of calcium absorption. What is needed is a form of 1,25(OH)2D3 that is in a prodrug form so that when it is taken orally it does not have a first pass biologic effect on the intestine. In addition, if the prodrug form of 1,25(OH)2D3 had increased water solubility, it could be formulated in a cream for the treatment of psoriasis. The goal of this feasibility phase I proposal is to chemically synthesize two glycoside derivatives of 1,25(OH)2D3 including 1,25(OH)2D3 -3beta-glucoside, and 1,25(OH)2D3-maltoside. Once these compounds have been synthesized, their water solubility will be investigated along with their biologic activity in vitro.