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been replaced by a carbon, resulting in a metabolically stable P-C-P structure.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.