1,25-Dihydroxyvitamin D3 and its analogs have proven to be useful as pharmacologic agents for a variety of diseases. I ,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. 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. 1,25(0H)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(0H)2D3 has also been demonstrated to be extremely effective both orally and topically for the treatment of psoriasis. However, since 1,25(0H)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(0H)2D,3, when given orally, interacts directly with the small intestine to raise the efficiency of calcium absorption. A form of 1,25(0H)2D3, that is in a prodrug form, is needed, so 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(0H)2D3 had increased water solubility, it could be formulated in a cream for the treatment of psoriasis. The goal of Phase I is to chemically synthesize two glycoside derivatives of 1,25(0H)2D3 including 1,25(0H)2D3 -3beta-glucoside, and 1,25(0H)2D3-maltoside. Once these compounds have been synthesized, their water solubility will be investigated along with their biologic activity in vitro.Awardee's statement of the potential commercial applications of the research: Prodrugs of 1,25(0H)2D3 such as 1,25(0H)2D3-glycoside that do not have a direct first pass biologic action on the intestine could be of great benefit for treating metabolic bone diseases and the skin disease psoriasis because they would have less of a calcemic action permitting higher blood concentrations of 1,25(0H)2D3 to be obtained. Glycoside derivatives of 1,25(0H)2D3 will have increased water solubility, and, therefore, can be formulated in a more desirable cream based preparation for topical use for psoriasis. (subscript "2" and "3" after (OH) and D, respectively)National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
