Nitrogenous bisphosphonates

Bisphosphonates (BP) are today the first line treatment of benign and malignant bone diseases. As pyrophosphate analogues (Fig. 3), BP accumulate in bone and are taken up by osteoclasts. Once in the cell, the nitrogen-containing BP (N-BP) such as Alendronate, Risedronate, Ibandronate and Zoledronate effectively inhibit osteoclast resorption and induce cell... 

Fig. 15.5 Some isoprenoid diphosphate carbocation intermediates involved in cholesterol biosynthesis, along with some nitrogen containing bisphosphonates, their proposed transition-state-analogues. (DMAPP = dimethylallyl diphosphate,...

Glickman, J.F. and A. Schmid. 2007. Famesyl pyrophosphate synthase real-time kinetics and inhibition by nitrogen-containing bisphosphonates in a scintillation assay. Assay Drug Dev. Technol. 5, 205-214. 

Dunford, J.E., Thompson, K., Coxon, F.P., Luckman, S.P., Hahn, F.M., Poulter, C.D., Ebetino, F.H., and Rogers, M.J. (2001). Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296 235-242. 

Oades, G.M., Senaratne, S.G., Clarke, I.A., Kirby, R.S., and Colston, K.W. (2003). Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol 170 246-252. 

Forsea, A.M., Muller, C., Riebeling, C., Orfanos, C.E., and GeUen, C.C. (2004). Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells. Br J Cancer 91 803-810. 

Huang, C.H., Gabelli, S.B., Oldfield, E., and Amzel, L.M. (2010). Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. Proteins 78 888-899. 

Tlie clinical utility of another first-generation, non-nitrogen-containing bisphosphonate, tiludronate, has been limited because of concern over renal adverse effects observed in early trials. In a dose-finding study for the treatment of HCM, 19 patients received i.v. drug followed by oral maintenance therapy [70]. Three patients had elevated serum creatinine levels after i.v. drug administration of 4.5 or 6.0 mg/kg, 1 of whom developed acute renal insufficiency and subsequently died, most probably due to tiludronate, although renal infection and allopurinol therapy could have played a contributory role. 

In comparison with the results obtained with earlier bisphosphonates, clinical trials with the nitrogen-containing bisphosphonate pamidronate in more than 1, 300 patients with cancer have reported greater efficacy without a concomitant increase in renal toxicity. 

Although the 2,4-dinitrohydrazone free acid is relatively stable in water, the 2-methoxy 4-nitrophenylhydrazone decomposes at acid or near neutral pH, as does the unsubstituted phenylhydrazone, to a mixture of phosphate and cyanophosphate. This can be rationalized as a fragmentation involving cleavage of both a P-C bond of the bisphosphonate and the N-N bond of the hydrazone, with an aniline as the leaving group. The basicity of the nascent amino nitrogen... 

FIGURE 30.6 Examples of protein crystals. From left to right (3-secretase inhibitor complex human farnesyl pyrophosphatase in complex with the nitrogen-containing bisphosphonate drug zoledronic acid Crystals of the Abl kinase domain in complex with imatinib - Source Courtesy of S.W. Cowan-Jacob, Novartis Institutes for BioMedical Research crystal of a Cdk2 inhibitor complex. 

Figure 2.38 The nickel bisphosphonate Ni2(03PCH2NC4HsNCH2PO3).2H2O possesses channels 1 nm in free dimension. Edge-sharing helical chains of NiOsN octahedra are linked by piperazine units the bisphosphonic acid coordinates to the nickel by both oxygen and nitrogen atoms.

The nitrogen-containing bisphosphonates (A-BPs) constitute the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of A-BPs is farnesylpyrophosphate... 

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