An ADAM10 exosite inhibitor is efficacious in an in vivo collagen-induced arthritis model

Abstract

Abstract Rheumatoid arthritis is a systemic autoimmune inflammatory disease which affects millions of people worldwide. There are multiple disease-modifying anti-rheumatic drugs available; however, many of the patients do not respond to any treatment. A disintegrin and metalloproteinase 10 has been suggested as a potential new target for RA due to its role in releasing of multiple pro- and anti-inflammatory factors from the cell surface of cells. In the present study we determined pharmacokinetic parameters and in vivo efficacy of a compound CID3117694 from a novel class of non-zinc-binding inhibitors. Oral bioavailability was demonstrated in blood and synovial fluid after 10mg/kg dose. To test efficacy, we established the collagen-induced arthritis model in mice. CID3117694 was administered orally at 10, 30, and 50 mg/kg/day for 28 days. CID3117694 was able to dose-dependently improve disease score, decrease RA markers in blood and decrease signs of inflammation, hyperplasia, pannus formation, and cartilage erosion in affected joints as compared to the untreated control. Additionally, mice treated with CID 3117694 did not exhibit any clinical signs of distress, suggesting low toxicity. The results of this study suggest that ADAM10 exosite inhibition can be a viable therapeutic approach to RA.