title: Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
abstract: 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.
authors: Upjohn Company, Kalamazoo, Michigan 49001.
authors: R A
authors: RA
authors: Nugent
authors: S T
authors: ST
authors: Schlachter
authors: M
authors: M
authors: Murphy
authors: C J
authors: CJ
authors: Dunn
authors: N D
authors: ND
authors: Staite
authors: L A
authors: LA
authors: Galinet
authors: S K
authors: SK
authors: Shields
authors: H
authors: H
authors: Wu
authors: D G
authors: DG
authors: Aspar
authors: K A
authors: KA
authors: Richard
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004164:Diphosphonates