Linking bisphosphonates to the free amino groups in fluoroquinolones: preparation of osteotropic prodrugs for the prevention of osteomyelitis.
Osteomyelitis is an infection located in bone and a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered antibiotics. Targeting antibiotics to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. By taking advantage of the affinity of the bisphosphonate group for bone mineral, we have prepared a set of 13 bisphosphonated antibacterial prodrugs based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. While all but one of the prodrugs were shown in vitro to be effective and rapid bone binders (over 90% in 1 h), only eight of them demonstrated the capacity to significantly regenerate the parent drug. In a rat model of the disease, a selected group of agents demonstrated their ability to prevent osteomyelitis when used in circumstances under which the parent drug had already been cleared and is thus inactive.
Houghton
Tom J
TJ
Targanta Therapeutics Inc, 7170 Avenue Frederick Banting, St. Laurent, Québec, H4S 2A1, Canada.
Tanaka
Kelly S E
KS
Kang
Ting
T
Dietrich
Evelyne
E
Lafontaine
Yanick
Y
Delorme
Daniel
D
Ferreira
Sandra S
SS
Viens
Frederic
F
Arhin
Francis F
FF
Sarmiento
Ingrid
I
Lehoux
Dario
D
Fadhil
Ibtihal
I
Laquerre
Karine
K
Liu
Jing
J
Ostiguy
Valérie
V
Poirier
Hugo
H
Moeck
Gregory
G
Parr
Thomas R
TR
Far
Adel Rafai
AR
D000588:Amines / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010019:Osteomyelitis / Q000517:prevention & control*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000588:Amines; D004164:Diphosphonates; D024841:Fluoroquinolones; D011355:Prodrugs