TMI 1

一种ADAM和MMP抑制剂；在无细胞酶实验中抑制ADAM17/TACE（IC₅₀=8.4 nM）；在体外抑制MMP-1、-2、-7、-9、-13和-14以及ADAM-TS-4（IC₅₀分别为6.6nM、4.7nM、26nM、12nM、3nM、26nM和100nM）；在无细胞酶实验中抑制ADAM8、-10、-12和-17/TACE（Ki分别为21nM、16nM、1.8nM和0.079nM）。此外，该化合物抑制LPS诱导的TNF-α分泌，在Raw和THP-1细胞中IC₅₀分别为40nM和200nM，也在分离的人单核细胞和全血中表现出抑制作用（IC₅₀分别为190nM和300nM）。它还能在体外抑制类风湿性关节炎患者炎症关节滑膜中TNF-α的产生（IC₅₀=50nM），并在胶原诱导性关节炎小鼠模型中减轻疾病严重程度。在MMTV-ErbB2/neu乳腺癌小鼠模型中，以100mg/kg剂量给药，降低细胞活性（ED₅₀为1.3-8.1µM），诱导肿瘤凋亡并减少肿瘤生长。An ADAM and MMP inhibitor; inhibits ADAM17/TACE (IC50 = 8.4 nM in a cell-free enzyme assay); inhibits MMP-1, -2, -7, -9, -13, and -14, as well as ADAM-TS-4 in vitro (IC50s = 6.6, 4.7, 26, 12, 3, 26, and 100 nM, respectively); inhibits ADAM8, -10, -12, and -17/TACE (Kis = 21, 16, 1.8, and 0.079 nM, respectively, in cell-free enzyme assays); inhibits LPS-induced TNF-α secretion in Raw and THP-1 cells (IC50s = 40 and 200 nM, respectively), as well as in isolated human monocytes and whole blood (IC50s = 190 and 300 nM, respectively); inhibits the production of TNF-α ex vivo in synovium isolated from the inflamed joints of patients with rheumatoid arthritis (IC50s = 50 = 5 mg/kg) and reduces disease severity in mouse models of collagen-induced arthritis; decreases cell viability of (ED50s = 1.3-8.1 µM) and induces tumor apoptosis and reduces tumor growth in an MMTV-ErbB2/neu mouse model of breast cancer at 100 mg/kg.