Selective inhibitors of vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity

The vacuolar proton pump located on the ruffled border of the osteoclast is essential to the bone resorption process since it provides the acidity req uired for the dissolution of bone mineral and for assisting matrix degradat ion by collagenases that operate at acidic pH. Therefore, this enzyme has b een considered as a potential molecular target for the design of novel bone antiresorptive agents useful for the treatment of osteoporosis and other m etabolic diseases of bone. The discovery of novel inhibitors has been hampe red by the high complexity and incomplete structural knowledge of-the pump. However, in the last few years, a few patent applications and publications have appeared in the literature describing novel compounds able to inhibit the osteoclast enzyme and therefore, bone resorption. These include natura l products, synthetically modified natural products, or compounds derived f rom inhibitors of the gastric H+/K+-ATPase or designed de novo using a rati onal design. Biological data are very few in the patent literature and, the refore, it is difficult to assess the validity of these new inhibitors. How ever, one or two classes look very promising showing very good selectivity and high efficacy. These results will possibly stimulate further research i n the field.