ANTICALCIFICATION AND ANTIRESORPTION EFFECTS OF BISACYLPHOSPHONATES

Some geminal bisphosphonates are used clinically in a number of import ant bone and calcium-related diseases. This work reports the anticalci fication and antiresorption effects of a series of bisacylphosphonates , nongeminal compounds with varying chain lengths having oxo groups in or positions relative to the phosphonic functions. We compared the ac tivity of the novel compounds to clinically used geminal bisphosphonat es, and to a bisphosphonate devoid of the oxo groups. The interaction of the compounds with calcium was studied by various in vitro and in v ivo models. We found that keto groups in cw positions to the phosphoni c functions render activity. The bisacylphosphonates with a shorter ch ain [(CH2)n, = 4, 6] were found significantly to inhibit hydroxyapatit e formation and dissolution in vitro, the calcification of bioprosthet ic tissue implanted subdermally in rats, and bone resorption in the in tact young animal model. The various in vitro results were found to be in good correlation with the in vivo results. Structure-activity rela tionship studies indicate that both bisacylphosphonates and geminal bi sphosphonates are active only when at least three ionizable groups are present in the molecule. The role of the keto groups is related to th eir contribution to chelating calcium and/or to their electron-withdra wing influence on acidity.