Thionapthene-2-carboxylic acid: a new antihypercalcemic agent.

Thiophene-2-carboxylic acid (TCA) was previously shown to be hypocalcemic in the rat. We have compared TCA with thionapthene-2-carboxylic acid (TNCA), an analog which is a more potent inhibitor of bone resorption in vitro, for the ability to decrease serum calcium concentration in vivo. In normocalcemic rats on a low calcium diet, TNCA (2 mmol/kg) produced a larger and more prolonged decrease in calcium concentration than TCA. In rats bearing the Walker 256 carcinosarcoma, which became hypercalcemic, TNCA produced a dose-related decrease in serum calcium concentration at 0.3-1.2 mmol/kg. TNCA reduced serum calcium concentration in 4-6 h, and the effects were sustained for up to 72 h. TNCA was effective after oral as well as sc administration. Unlike calcitonin which produced only a transient reduction in serum calcium followed by escape, the effects of TNCA (0.6 mmol/kg) were sustained for 1 week and were accompanied by a decrease in mortality in tumor-bearing animals. We conclude that TNCA is a potent hypocalcemic action which has a rapid and prolonged effect without evidence of escape. This and related compounds should be tested further for use in treatment of hypercalcemia and other states characterized by excessive bone resorption.