2-SULFINYL BENZOTHIAZOLES, BENZOXAZOLES AND BENZIMIDAZOLES ARE NOVEL IN-VITRO BONE ANTI-REABSORPTIVE COMPOUNDS

Bone resorption by osteoclasts is dependent on H+ transport into the e xternal resorption lacunae, generating an acidic microenvironment in w hich bone mineral dissolution and matrix degradation occur. A vacuolar H+-ATPase is responsible for osteoclast H+ secretion. Here, we descri be novel vacuolar H+-ATPase inhibitors that inhibit bone resorption in vitro. Several agents inhibited Ca-45 release from mouse calvariae, H -3-proline release from bone particles by chicken osteoclast-like cell s, and resorption pit formation by murine osteoclasts on dentine slice s. One compound, a 2-sulfinylbenzothiazole (XS238), is significantly m ore potent than previously reported vacuolar H+-ATPase inhibitors, exh ibiting an IC50 of 5 mu M in the Ca-45 release assay, an IC50 of 1 mu M in the H-3-proline release assay, and an IC50 of 100 nM in the resor ption pit assay. The potent H+-ATPase inhibitors described may have va lue in treating osteoporosis and other bone diseases.