Current drug therapy for hypercalcemic diseases involving bone resorption is of limited effectiveness. Preliminary animal testing has shown benzo(b)thiophene-2-carboxylic acid (thionapthenecarboxylic acid, TNCA) to be of potential use in inhibiting bone resorption. Overall project goals are to develop TNCA and its derivatives as novel therapeutic entities in the treatment of hypercalcemia of malignancy, hypercalcemia of primary hyperparathyroidism, Paget's Disease, arthritis a osteoporosis. TNCA's use application potentially extends to bone calcium loss suffered in stratospheric residence. Specific Phase I activities include the testing of a novel water- soluble derivative of TNCA in a number of in vivo biological test systems, such as rats with Leydig cell tumors and Walker 256 carcinosarcomas. Animals will be evaluated for survival, bone changes, and toxic effects. Selected animals will be examined histologically for changes in bone resorption based upon the number of osteoclasts and resorption lacunae. In addition, several new and novel tetracycline and phosphonate derivatives will be synthesized and evaluated in a tissue culture test model of bone cells. The new derivatives will also be tested in tissue culture models.
