Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
Nugent
R A
RA
Upjohn Company, Kalamazoo, Michigan 49001.
Schlachter
S T
ST
Murphy
M
M
Dunn
C J
CJ
Staite
N D
ND
Galinet
L A
LA
Shields
S K
SK
Wu
H
H
Aspar
D G
DG
Richard
K A
KA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001168:Arthritis / Q000188:drug therapy*; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004164:Diphosphonates