Bisphosphonates and novel related structural classes for bone resorption disorders

Bisphosphonates (BPs) are powerful inhibitors of bone resorption. They exer t a strong affinity to bone mineral which allows the rapid and selective ta rgeting to bone in vivo. We synthesized and evaluated two new classes of co mpounds: phosphono succinic acid (PSA) and phosphono glutaric acid (PGA) de rivatives. In order to transfer the antiresorptive properties of bisphospho nates attempts have been made to elucidate the key elements of the putative BP pharmacophore. Whereas the new compounds revealed similar or better bon e mineral affinity properties than BPs in vitro, the inhibition of endogeno us bone resorption in vivo was less effective, but in contrast to BPs the e ffects were reversible after discontinuation of treatment, which suggests t hat these compounds are metabolically degradable.