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(i)s 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.
- Binding Sites
- Enzyme Inhibitors
- Models, Molecular
- Molecular Structure
- Structure-Activity Relationship
- Time Factors
Dunford, J. E., Kwaasi, A. A., Rogers, M. J., Barnett, B. L., Ebetino, F. H., Russell, R. G. G., Oppermann, U., & Kavanagh, K. L. (2008). Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. Journal of Medicinal Chemistry, 51(7), 2187-2195. https://doi.org/10.1021/jm7015733