Patent Evaluation: Agents which Interfere with IL-1 for the Treatment of Arthritis

Summary

Novelty: The use of misoprostol to inhibit cartilage damage or enhance repair of cartilage is described (GB2241436; GD Searle). It functions by inhibiting the actions of IL-1 (e.g. cartilage synthesis). In US5039695, Merrell Dow discloses N-aryl or heteroaryl-alkyl-pyrrole-2-carboxylic acids as IL-1 inhibitors. They are claimed for the treatment of rheumatoid arthritis, psoriasis and atherosclerosis.

Biology: The effect of misoprostal on pig articular organ cultures is presented and in GB2241436 shown to overcome the IL-1 induced loss of GAG content from 68% loss to 4% over 8 days (at 200 ng/ml). Similar effects are shown on cartilage taken from human patients. 50% inhibition of GAG synthesis is observed at only 0.01 ng/ml IL-1-α). A table shows the effect of misoprostol (at 0.1–100 ng/ml). Hisoprostol appears most effective when levels of IL-1 are less than 0.1 ng/ml. An ex vivo assay for IL-1 secretion by mouse macrophages is described in US5039695 (67–95% inhibition at 100 mg/kg, po).

Chemistry: Three synthetic examples are described in US5039695. The preferred compound is 1([1,1′-biphenyl]-4-ylmethyl)-1H-pyrrole-2-carboxylic acid.