LY-221068

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.