التفاصيل البيبلوغرافية
| العنوان: |
Characterization of (2R, 3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-α converting enzyme |
| المؤلفون: |
Zhang, Yuhua yzhang@wyeth.com, Hegen, Martin1, Xu, Jun2, Keith, James C.1, Jin, Guixian2, Du, Xuemei2, Cummons, Terri2, Sheppard, Barbara J.1, Sun, LinHong1, Zhu, Yi1, Rao, Vikram R.1, Wang, Qin1, Xu, Weixin1, Cowling, Rebecca2, Nickerson-Nutter, Cheryl L.1, Gibbons, Jay2, Skotnicki, Jerry2, Lin, Lih-Ling1, Levin, Jeremy2 |
| المصدر: |
International Immunopharmacology. Dec2004, Vol. 4 Issue 14, p1845-1857. 13p. |
| مصطلحات موضوعية: |
*TUMOR necrosis factors, *MACROPHAGES, *ENZYMES, *CONNECTIVE tissues, *IMMUNOLOGIC diseases, *MICE |
| مستخلص: |
TNF-α converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-α (TNF-α) inhibitors. Here we report the pre-clinical results and characterization of a selective and potent TACE inhibitor, (2R, 3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide (TMI-2), in various in vitro and in vivo assays. TMI-2 is a potent TACE inhibitor in an enzymatic FRET assay (IC50=2 nM). It is more than 250-fold selective over MMP-1, -7, -9, -14, and ADAM-10 in vitro. In cell-based assays and human whole blood, TMI-2 inhibits lipopolysaccharide (LPS)-induced TNF secretion with IC50s<1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-α in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 μM. In vivo, TMI-2 potently inhibits LPS-induced TNF-α production in mice (ED50=3 mg/kg). In the adjuvant-induced arthritis (AIA) model in rats, treatment with TMI-2 at 30 mg/kg and 100 mg/kg p.o. b.i.d. was highly effective in reducing joint arthritis scores. In a semi-therapeutic collagen-induced arthritis (CIA) model in mice, TMI-2 is highly effective in reducing disease severity scores after oral treatment at 100 mg/kg twice per day. In summary, TMI-2 is a potent and selective TACE inhibitor that inhibits TNF-α production and reduces the arthritis scores in pre-clinical models. TMI-2 represents a novel class of TACE inhibitors that may be effective and beneficial in the treatment of rheumatoid arthritis as well as other TNF-mediated inflammatory autoimmune diseases. [Copyright &y& Elsevier] |
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