Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)

Abstract

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

“…The presence of unlabeled PAM is not seen as problematic because it is less than the minimum clinical dose required to affect bone resorption. 14 C radiography remains a valuable gold standard for bisphosphonate quantification, but it has its limitations because it is not possible to visualize 14 C-ZA at a cellular level. (21) In contrast, AlexaPam647 could be visualized inside resorbing osteoclasts (Fig.…”

“…Furthermore, the approach of direct imaging of BP on bisected bones using confocal microscopy minimized postprocessing and allowed for rapid imaging. Co-localization between 14 C-ZA and AlexaPam647 suggests that the dynamics of these BPs are similar, despite their potential differing potency for FPP synthase inhibition, (22) with ZA being the more potent agent. Previous studies have noted subtle differences in binding and localization between low-affinity residronate analogues; (23) however, no overt differences were found between AlexaPam647 fluorescent images and 14 C-ZA autoradiographs (Fig.…”

“…As an alternate imaging modality, 14 C radiolabeled ZA included in the BP mixture was examined by autoradiography on bisected femora. When overlaid with AlexaPam647 fluorescence, the two images showed comparable patterns of distribution (Fig.…”

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

“…However, the effects of YM175 and YM529 were impaired against a P-gp-overexpressing osteosarcoma cell line (Horie et al, 2006). As YM529 has not been made clinically available yet we investigated the anti-osteosarcoma effects of ZOL, another thirdgeneration BP, which is clinically available and as potent as YM529 at inhibiting bone resorption in vivo (Widler et al, 2002). To investigate specificity of ZOL against osteosarcoma cells, we examined the inhibitory effects of ZOL against both osteosarcoma cell lines and normal cells such as murine osteoblast and NHDF cells.…”

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

“…These metabolites accumulate in the cell cytoplasm with consequent inhibition of numerous intracellular metabolic enzymes, resulting in detrimental effects on cell function and survival. The latter, which is typical of second and third generation N-BPs ( Figure 1, N-aliphatic and N-heteroaromatic respectively) 7 is the blockade of protein prenylation due to their ability to inhibit the mevalonate pathway. The main biochemical target of bisphosphonates is farnesyl pyrophosphate synthase (FPPS), an enzyme of the presqualenic part of the sterol biosynthetic pathway.…”