2-sulfinyl benzothiazoles, -oxazoles and -imidazoles are novel in vitro bone anti-reabsorptive compounds

Bone resorption by osteoclasts is dependent on H+ transport into the external resorption lacunae, generating an acidic microenvironment in which bone mineral dissolution and matrix degradation occur. A vacuolar H+-ATPase is responsible for osteoclast H+ secretion. Here, we describe 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 cells, and resorption pit formation by murine osteoclasts on dentine slices. One compound, a 2-sulfinylbenzothiazole (XS238), is significantly more potent than previously reported vacuolar H+-ATPase inhibitors, exhibiting 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 resorption pit assay. The potent H+-ATPase inhibitors described may have value in treating osteoporosis and other bone diseases.