PDF(Pubmed)
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.
摘要：
类风湿性关节炎是一种全身性自身免疫性炎性疾病，影响全球数百万人。有多种改善疾病的抗风湿药物可用；然而，许多患者对任何治疗都没有反应。由于解整合素和金属蛋白酶10在从细胞表面释放多种促炎和抗炎因子中的作用，因此已被认为是RA的潜在新靶标。在本研究中,我们测定了一类新型非锌结合抑制剂的化合物CID3117694的药代动力学参数和体内疗效.口服生物利用度在10mg/kg剂量后在血液和滑液中得到证实。为了测试功效，我们建立了胶原诱导的小鼠关节炎模型。CID3117694以10、30和50mg/kg/天口服给药28天。CID3117694能够剂量依赖性地改善疾病评分，减少血液中的RA标记，减少炎症的迹象，增生,血管nus形成,与未治疗的对照相比，受影响的关节中的软骨侵蚀。此外,用CID3117694治疗的小鼠没有表现出任何临床症状，表明低毒性。这项研究的结果表明，抑制ADAM10exosite可以是RA的可行治疗方法。
