An ADAM10 Exosite Inhibitor Is Efficacious in an In Vivo Collagen-Induced Arthritis Model
Juan Diez1, Michael E Selsted2, Thomas D Bannister3
1Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3321 College Avenue, Fort Lauderdale, FL 33314, USA.
Abstract:
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.
Insights
A novel drug, CID3117694, shows promise for rheumatoid arthritis (RA) treatment by inhibiting ADAM10. This compound effectively reduced RA symptoms and inflammation in mice with minimal toxicity, suggesting a new therapeutic avenue.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is a widespread autoimmune disease impacting millions globally.
- Current disease-modifying anti-rheumatic drugs (DMARDs) have limited efficacy for many RA patients.
- ADAM10 (a disintegrin and metalloproteinase 10) is implicated in inflammatory factor release, presenting a potential therapeutic target for RA.
Purpose of the Study:
- To evaluate the pharmacokinetic properties and in vivo efficacy of CID3117694, a novel non-zinc-binding inhibitor targeting ADAM10.
- To assess the therapeutic potential of inhibiting ADAM10 exosite in a preclinical model of rheumatoid arthritis.
Main Methods:
- Pharmacokinetic analysis of CID3117694 after oral administration in mice.
- Assessment of CID3117694 efficacy in the collagen-induced arthritis (CIA) mouse model.
- Dose-dependent administration of CID3117694 (10, 30, 50 mg/kg/day) for 28 days, monitoring disease score, RA markers, and joint pathology.
Main Results:
- CID3117694 demonstrated oral bioavailability in blood and synovial fluid.
- The compound significantly and dose-dependently improved disease scores in CIA mice.
- CID3117694 reduced RA markers, inflammation, hyperplasia, pannus formation, and cartilage erosion.
- No clinical signs of distress were observed, indicating low toxicity of CID3117694.
Conclusions:
- Inhibition of ADAM10 exosite by CID3117694 is a promising therapeutic strategy for rheumatoid arthritis.
- CID3117694 exhibits favorable pharmacokinetics and potent anti-arthritic effects in vivo.
- The findings support further development of ADAM10 inhibitors for RA treatment.
