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 ⁴⁵Ca release from mouse calvariae, ³H-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 μM in the ⁴⁵Ca release assay, an IC₅₀ of 1 μM in the ³H-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.