TMI 1

TMI 1 is an inhibitor of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17/TACE, IC50 = 8.4 nM in a cell-free enzyme assay). It inhibits matrix metalloproteinase-1 (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). It also inhibits ADAM8, -10, -12, and -17/TACE in cell-free enzyme assays with Ki values of 21, 16, 1.8, and 0.079 nM, respectively, with slow-binding inhibition of ADAM17/TACE but not the other ADAM enzymes. TMI 1 inhibits LPS-induced TNF-alpha 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). It inhibits the production of TNF-alpha ex vivo in synovium isolated from the inflamed joints of patients with rheumatoid arthritis with IC50 values of less than 100 nM without inhibiting TNF-alpha expression in vitro. TMI 1 inhibits LPS-induced TNF-alpha production in mice (ED50 = 5 mg/kg) and reduces disease severity in mouse models of collagen-induced arthritis. It also decreases cell viability of (ED50s = 1.3-8.1 µM), and induces caspase-3/7 activity in, a variety of cancer cell lines and induces tumor apoptosis and reduces tumor growth in an MMTV-ErbB2/neu mouse model of breast cancer when administered at a dose of 100 mg/kg.Formal Name: (3S)-4-[[4-(2-butyn-1-yloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide. CAS Number: 287403-39-8. Molecular Formula: C17H22N2O5S2. Formula Weight: 398.5. Purity: >98%. Formulation: (Request formulation change), A solid. Solubility: DMSO: 25 mg/ml. SMILES: CC#CCOC1=CC=C(S(N2CCSC(C)(C)[C@@H]2C(NO)=O)(=O)=O)C=C1. InChi Code: InChI=1S/C17H22N2O5S2/c1-4-5-11-24-13-6-8-14(9-7-13)26(22,23)19-10-12-25-17(2,3)15(19)16(20)18-21/h6-9,15,21H,10-12H2,1-3H3,(H,18,20)/t15-/m0/s1. InChi Key: CVZIHNYAZLXRRS-HNNXBMFYSA-N.