Structure–Activity Relationships Among the Nitrogen Containing Bisphosphonates in Clinical Use and Other Analogues: Time-Dependent Inhibition of Human Farnesyl Pyrophosphate Synthase

The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K is and calculating the isomerization constant K isom for many N-BPs. Disruption of the phosphonate−carbon−phosphonate backbone resulted in loss of potency and reduced K isom. The lack of a hydroxyl group on the geminal carbon also reduced K isom. The position of the nitrogen in the side chain was crucial to both K i and K isom. A correlation of K isom and also final K i with previously published in vivo potency reveals that the isomerization constant (R = −0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs (R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.