Discovery of Coumarin–Dihydropyridine Hybrids as Bone Anabolic Agents

The concept of molecular hybridization led us to discover a novel series of coumarin–dihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds <b>10</b>, <b>14</b>, <b>18</b>, and <b>22</b> showed significant activity at picomolar concentrations. A series of other in vitro data strongly suggested compound <b>18</b> as the most promising bone anabolic agent, which was further evaluated for in vivo studies. From these studies compound <b>18</b> proved to be useful, which at low oral dose of 1 (mg/kg)/day body weight increased bone mass density and volume, expression of osteogenic genes (RUNX2, BMP-2, and ColI), bone formation rate (BFR), and mineral apposition rate (MAR), improved the trabecular microarchitecture, and decreased bone turn over markers in an ovariectomized rodent model for postmenopausal osteoporosis