LY 221068 and LY 269415 are representative compounds from a chemical series of 4-aminothiazolidines, with potent antioxidant properties in vitro. We have evaluated these two compounds in a rat model of articular inflammation caused by the administration of recombinant human IL-1 beta into the knee joints. IL-1 injection into the knee joints has been shown to cause a complex series of changes resulting in synovitis, mesenchymal proliferation, and subchondral bone and cartilage erosion. The inflammatory response of the knee joint was measured by determining the changes in the joint swelling and also by histological evaluation of the knee joints. Rats pretreated (p.o.) with 10-25 mg/kg of either of these compounds (4 h prior to IL-1 injection) displayed greatly reduced soft tissue swelling with an IC50 of 7.5 mg/kg. Evaluation of histological lesions revealed, however, that LY 269415 (IC50 of 10 mg/kg) was more potent than LY 221068 (IC50 of 25 mg/kg) in reducing the severity of histological changes. The results demonstrate that antioxidants of this chemical series either directly or indirectly display anti-inflammatory properties and could be beneficial as therapeutic agents in inflammatory arthritis.

01 Nov 1993·Annals of the New York Academy of SciencesQ2 · CROSS-FIELD

4‐Thiazolidinones, Potent Antioxidants, as Antiinflammatory Agents

Q2 · CROSS-FIELD

Article

Author: D. N. Benslay ; M. L. Phillips ; J. A. Panetta ; P. P. K. Ho ; J. K. Shadle

The anti-inflammatory effects of the antioxidants 4-thiazolidinones were studied in rats with Freund's complete adjuvant-induced arthritis.Results indicated LY 221068 and LY 269415 are the most promising compoundsThe results also support the hypothesis that reactive oxygen species/lipid peroxidation may play an important role in pathogenesis of rheumatoid arthritis.

01 Sep 1991·Agents and Actions

Anti-inflammatory effects of LY221068 and LY269415

Article

Author: R. D. Towner ; J. A. Panetta ; J. K. Shadle ; P. P. K. Ho ; D. N. Benslay

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Arthritis	Discovery	US	Eli Lilly & Co.	-

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