The discovery of the bone-active agent risedronate, and bisphosphonate structure-activity considerations including the aminophenylethane phosphonate series

Risedronate was selected for clinical development from a library of more th an 200 bisphosphonate analogs for the treatment of a variety of bone diseas es. It is a pyridinyl bisphosphonate and is therefore characterized by a ni trogen residue in its structure. Our studies have increased the understandi ng of the optimal spatial arrangement of the nitrogen and phosphonate moiet ies required to give the bisphosphonate molecules the geometry necessary fo r potent antiresorptive activity on bone. A series of aminophenylethane pho sphonates have been studied to further demonstrate these geometric requirem ents.