title: 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abstract: Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure.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.
authors.affiliation: Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, CH-4002 Basel, Switzerland. leo.widler@pharma.novartis.com
authors.forename: Leo
authors.initials: L
authors.lastname: Widler
authors.forename: Knut A
authors.initials: KA
authors.lastname: Jaeggi
authors.forename: Markus
authors.initials: M
authors.lastname: Glatt
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: Rolf
authors.initials: R
authors.lastname: Bachmann
authors.forename: Michael
authors.initials: M
authors.lastname: Bisping
authors.forename: Anne-Ruth
authors.initials: AR
authors.lastname: Born
authors.forename: Reto
authors.initials: R
authors.lastname: Cortesi
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guiglia
authors.forename: Heidi
authors.initials: H
authors.lastname: Jeker
authors.forename: Rémy
authors.initials: R
authors.lastname: Klein
authors.forename: Ueli
authors.initials: U
authors.lastname: Ramseier
authors.forename: Johann
authors.initials: J
authors.lastname: Schmid
authors.forename: Gerard
authors.initials: G
authors.lastname: Schreiber
authors.forename: Yves
authors.initials: Y
authors.lastname: Seltenmeyer
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Green
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D002117:Calcitriol; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006934:Hypercalcemia / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D000077268:Pamidronate; D016105:Parathyroidectomy; D051381:Rats; D012886:Skull / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013965:Thyroidectomy; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D002117:Calcitriol; D000077268:Pamidronate