| Autor: |
Tang ML; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China., Li H; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China., Ning JF; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China., Shen X; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China., Sun X; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.; The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China. |
| Abstrakt: |
Tumor necrosis factor α (TNF-α) has been demonstrated to be a therapeutic target for autoimmune diseases. However, this biological therapy exhibits some inevitable disadvantages, such as risk of infection. Thus, small-molecule alternatives by targeting TNF-α production signaling pathway are still in demand. Herein, we describe the design, synthesis, and structure-activity relationships of 3-aryindanone compounds regarding their modulation of TNF-α production. Among them, ( R )-STU104 exhibited the most potent inhibitory activity on TNF-α production, which suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4E signal pathways through binding with MKK3 and disrupting the TAK1 phosphorylating MKK3. As a result, ( R )-STU104 demonstrated remarkable dose-effect relationships on both acute and chronic mouse UC models. In addition to its good pharmacokinetic (PK) and safety profile, ( R )-STU104 showed better anti-UC efficacy in vivo at 10 mg/kg/d than mesalazine at the dose of 50 mg/kg/d. These results suggested that TAK1-MKK3 interaction inhibitors could be potentially utilized for the treatment of UC. |
