The Discovery of the Bone-Active Agent Risedronate, and Bisphosphonate Structure-Activity Considerations Including the Aminophenylethane Phosphonate Series

Abstract

Risedronate was selected for clinical development from a library of more than 200 bisphosphonate analogs for the treatment of a variety of bone diseases. It is a pyridinyl bisphosphonate and is therefore characterized by a nitrogen residue in its structure. Our studies have increased the understanding of the optimal spatial arrangement of the nitrogen and phosphonate moieties required to give the bisphosphonate molecules the geometry necessary for potent antiresorptive activity on bone. A series of aminophenylethane phosphonates have been studied to further demonstrate these geometric requirements.

Keywords::

• bisphosphonates
• risedronate
• antiresorptive activity
• bone disease
• structure-activity relationships
• aminophenylethane phosphonates