title: Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis.
abstract: As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence rates. Targeting antibiotics to the bone after systemic administration would present at least three potential advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater convenience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the affinity of the bisphosphonate group for bone for delivery to osseous tissues.
authors.affiliation: The Medicines Company, 7170 Avenue Frederick Banting, St. Laurent, Québec, Canada H4S 2A1.
authors.forename: Kelly S E
authors.initials: KS
authors.lastname: Tanaka
authors.forename: Evelyne
authors.initials: E
authors.lastname: Dietrich
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ciblat
authors.forename: Claude
authors.initials: C
authors.lastname: Métayer
authors.forename: Francis F
authors.initials: FF
authors.lastname: Arhin
authors.forename: Ingrid
authors.initials: I
authors.lastname: Sarmiento
authors.forename: Gregory
authors.initials: G
authors.lastname: Moeck
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
authors.forename: Adel Rafai
authors.initials: AR
authors.lastname: Far
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D000077427:Lipoglycopeptides; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010019:Osteomyelitis / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000627:therapeutic use / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D011355:Prodrugs; D014640:Vancomycin; C100708:oritavancin