tmi-1 and Disease-Models--Animal

A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.

Topics: Acetylene; ADAM Proteins; ADAM17 Protein; Administration, Oral; Alkynes; Animals; Arthritis; Caco-2 Cells; Collagen; Crystallography, X-Ray; Disease Models, Animal; Dogs; Enzyme Inhibitors; Haplorhini; Humans; Hydroxamic Acids; Lipopolysaccharides; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Mice; Molecular Structure; Morpholines; Propanols; Rats; Structure-Activity Relationship; Sulfonamides; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF)-alpha is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF-alpha is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF-alpha-converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-alpha. TACE inhibitors that prevent the secretion of soluble TNF-alpha may be effective in treating rheumatoid arthritis (RA) patients. Using a structure-based design approach, we have identified a novel dual TACE/matrix metalloprotease (MMP) inhibitor 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1). This molecule inhibits TACE and several MMPs with nanomolar IC(50) values in vitro. In cell-based assays such as monocyte cell lines, human primary monocytes, and human whole blood, it inhibits lipopolysaccharide (LPS)-induced TNF-alpha secretion at submicromolar concentrations, whereas there is no effect on the TNF-alpha mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF-alpha secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF-alpha secretion by human synovium tissue explants of RA patients. In vivo, TMI-1 is highly effective in reducing clinical severity scores in mouse prophylactic collagen-induced arthritis (CIA) at 5, 10, and 20 mg/kg p.o. b.i.d. and therapeutic CIA model at 100 mg/kg p.o. b.i.d. In summary, TMI-1, a dual TACE/MMP inhibitor, represents a unique class of orally bioavailable small molecule TNF inhibitors that may be effective and beneficial for treating RA.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Arthritis, Rheumatoid; Cells, Cultured; Disease Models, Animal; Drug Interactions; Enzyme Inhibitors; Female; Humans; Lipopolysaccharides; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloendopeptidases; Mice; Mice, Inbred DBA; Morpholines; RNA, Messenger; Synovial Membrane; Tumor Necrosis Factor-alpha