Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents.

The proton ATPase located on the apical membrane of the osteoclast is essential to the bone resorption process. This proton pump is, therefore, an attractive molecular target for the design of novel inhibitors of bone resorption, and potentially useful for the treatment of osteoporosis and related metabolic diseases of bone. Recently, several inhibitors with different degrees of selectivity for the osteoclast V-ATPase have been reported. In particular, systematic chemical modifications of the macrolide antibiotic bafilomycin A1 have identified the minimal structural requirements for activity and allowed the design of simplified analogues that demonstrate high potency and selectivity for the osteoclast enzyme.