An ADAM10 Exosite Inhibitor Is Efficacious in an In Vivo Collagen-Induced Arthritis Model.
Juan DiezMichael E SelstedThomas D BannisterDmitriy MinondPublished in: Pharmaceuticals (Basel, Switzerland) (2024)
Rheumatoid arthritis is a systemic autoimmune inflammatory disease that affects millions of people worldwide. There are multiple disease-modifying anti-rheumatic drugs available; however, many 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 the release of multiple pro- and anti-inflammatory factors from cell surfaces. In the present study, we determined the pharmacokinetic parameters and in vivo efficacy of a compound CID3117694 from a novel class of non-zinc-binding inhibitors. Oral bioavailability was demonstrated in the blood and synovial fluid after a 10 mg/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 the disease score, decrease RA markers in the blood, and decrease signs of inflammation, hyperplasia, pannus formation, and cartilage erosion in the affected joints 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 the inhibition of ADAM10 exosite can be a viable therapeutic approach to RA.
Keyphrases
- rheumatoid arthritis
- disease activity
- oxidative stress
- anti inflammatory
- drug induced
- end stage renal disease
- ankylosing spondylitis
- interstitial lung disease
- diabetic rats
- newly diagnosed
- high glucose
- chronic kidney disease
- prognostic factors
- ejection fraction
- adipose tissue
- multiple sclerosis
- escherichia coli
- staphylococcus aureus
- metabolic syndrome
- risk assessment
- systemic lupus erythematosus
- patient reported outcomes
- type diabetes
- cell therapy
- skeletal muscle
- endothelial cells
- cystic fibrosis
- wound healing
- insulin resistance
- extracellular matrix
- binding protein
- patient reported
- idiopathic pulmonary fibrosis
- systemic sclerosis
- oxide nanoparticles