title: A General Strategy for Targeting Drugs to Bone.
abstract: Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland). wolfgang.jahnke@novartis.com.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Marzinzik
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Xavier
authors.initials: X
authors.lastname: Pellé
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Simona
authors.initials: S
authors.lastname: Cotesta
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourgier
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Henry
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: René
authors.initials: R
authors.lastname: Hemmig
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Stauffer
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: J Constanze D
authors.initials: JC
authors.lastname: Hartwieg
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Green
authors.affiliation: Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry and Oncology Research, 4002 Basel (Switzerland).
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase
keywords: AMP397 (becampanel); NMR spectroscopy; bone-affinity tag; drug delivery; tissue targeting