Nitrogen-containing bisphosphonate drugs

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. 

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. 

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. 

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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