1. Characterization of (2R, 3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-α converting enzyme
- Author
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Yi Zhu, Martin Hegen, Qin Wang, Jeremy I. Levin, Guixian Jin, Jay Gibbons, Xuemei Du, Lih-Ling Lin, James C. Keith, Rebecca Cowling, LinHong Sun, Terri Cummons, Yuhua Zhang, Jun Xu, Barbara J. Sheppard, J.S. Skotnicki, Cheryl Nickerson-Nutter, Weixin Xu, and Vikram R. Rao
- Subjects
Lipopolysaccharides ,medicine.medical_specialty ,Immunology ,Nuclease Protection Assays ,Biological Availability ,ADAM17 Protein ,In Vitro Techniques ,Cell Line ,Arthritis, Rheumatoid ,Mice ,In vivo ,Internal medicine ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Protease Inhibitors ,RNA, Messenger ,IC50 ,Whole blood ,Pharmacology ,Sulfonyl ,chemistry.chemical_classification ,Sulfonamides ,Synovitis ,biology ,Tumor Necrosis Factor-alpha ,business.industry ,Synovial Membrane ,Metalloendopeptidases ,Arthritis, Experimental ,Molecular biology ,In vitro ,Rats ,ADAM Proteins ,Endocrinology ,Enzyme ,chemistry ,Mice, Inbred DBA ,Rats, Inbred Lew ,Enzyme inhibitor ,Metalloproteases ,biology.protein ,Tumor necrosis factor alpha ,Collagen ,business - Abstract
TNF-alpha converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-alpha (TNF-alpha) 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 IC50s1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-alpha in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 microM. In vivo, TMI-2 potently inhibits LPS-induced TNF-alpha 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-alpha 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.
- Published
- 2004