The anti-inflammatory effects of LY178002 and LY256548.
LY178002 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinon e) and its N-methyl analog, LY256548, inhibit the enzymatic activity of phospholipase A2, 5-lipoxygenase and fatty acid cycloxygenase. They also inhibit leukotriene B4 production from human polymorphonuclear leukocytes stimulated with the calcium ionophore A23187. Since products of the arachidonic acid cascade have been implicated as important mediators in a variety of inflammatory diseases including arthritis, LY178002 and LY256548 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 was assessed of both the injected and uninjected paws. At 50 mg/kg LY178002 inhibited soft tissue swelling in the uninjected paw by 81% while LY256548 exhibited 57% inhibition. Bone damage was also significantly inhibited by both compounds. A dose response was conducted. The minimum effective dose for LY178002 was 10 mg/kg p.o. In the established FCA model LY178002 at 50 mg/kg p.o. inhibited the uninjected paw swelling by 75% while LY256548 did not show this level of activity. These results suggest that LY178002 and LY256548 may be useful in the treatment of arthritis.
Panetta
J A
JA
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Benslay
D N
DN
Phillips
M L
ML
Towner
R D
RD
Bertsch
B
B
Wang
L
L
Ho
P P
PP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001168:Arthritis; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D005620:Freund's Adjuvant; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009504:Neutrophils / Q000201:enzymology; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; C061317:LY 25648; C061319:LY 178002; D016718:Arachidonic Acid; D005620:Freund's Adjuvant