title: Anti-inflammatory effects of LY221068 and LY269415.
abstract: LY221068, 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxy phenyl]methylene]-3-(dimethylamino)-4-thiazolidinone, and the monomethylamino analog, LY269415, are anti-oxidants and potent inhibitors of iron dependent lipid peroxidation and 5-lipoxygenase enzyme. Since oxygen radical species, lipid peroxides and products of the arachidonic acid cascade have been implicated as important mediators in a variety of inflammatory diseases including arthritis, LY221068 and LY269415 were studied in the Freund's Complete Adjuvant Induced Arthritis (FCA) model in rats. The compounds were administered orally and inhibition of bone damage and paw swelling of both the injected and uninjected paws was assessed. At 50 mg/kg p.o., LY221068 inhibited soft tissue swelling in the uninjected paw by 72% while LY269415 at 25 mg/kg p.o. exhibited 74% inhibition. Bone damage was also significantly inhibited by both compounds. In a dose response study, the minimum effective dose for LY221068 was 10 mg/kg p.o. and for LY269415 was 5 mg/kg p.o. In the established FCA model in rats, LY221068 at 50 mg/kg p.o. inhibited the uninjected paw swelling by 71% while LY269415 at 25 mg/kg p.o. inhibited 70%. These results suggest that LY221068 and LY269415 may be useful in the treatment of arthritis.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indiannapolis, Indiana 46285.
authors.forename: J A
authors.initials: JA
authors.lastname: Panetta
authors.forename: D N
authors.initials: DN
authors.lastname: Benslay
authors.forename: J K
authors.initials: JK
authors.lastname: Shadle
authors.forename: R D
authors.initials: RD
authors.lastname: Towner
authors.forename: P P
authors.initials: PP
authors.lastname: Ho
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D000001:Calcimycin / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053778:Thiazolidines
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; C073113:LY 221068; C073114:LY 269415; D000001:Calcimycin; D011451:Prostaglandin-Endoperoxide Synthases