Molecular modeling and synthetic studies were carried out on several novel analogs of risedronate, a nitrogen-containing bisphosphonate (N-BP) drug that is widely used for the treatment of osteoporosis and other bone diseases. The physicochemical properties of the side-chain nitrogen and its position relative to the bisphosphonate P-C-P backbone are associated with the potency of N-BPs in inhibiting human farnesyl pyrophosphate synthase (FPPS), which is believed to be the biochemical target of these drugs. By computer-simulated docking with AutoDock 3 and predictive pKa calculation studies, we designed a small library of compounds to examine the relationship between nitrogen basicity and drug potency in risedronate analogs. A number of analogs, containing either electron-donating or electron-withdrawing substituents on the pyridinyl ring system, were evaluated for antiresorptivepotency in a standard assay.