title: Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis.
abstract: 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.
authors.affiliation: Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. yzhang@wyeth.com
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Levin
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.forename: Guangde
authors.initials: G
authors.lastname: Li
authors.forename: Heidi
authors.initials: H
authors.lastname: Robertshaw
authors.forename: Fionula
authors.initials: F
authors.lastname: Brennan
authors.forename: Terri
authors.initials: T
authors.lastname: Cummons
authors.forename: Dave
authors.initials: D
authors.lastname: Clarke
authors.forename: Nichole
authors.initials: N
authors.lastname: Vansell
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nickerson-Nutter
authors.forename: Dauphine
authors.initials: D
authors.lastname: Barone
authors.forename: Ken
authors.initials: K
authors.lastname: Mohler
authors.forename: Roy
authors.initials: R
authors.lastname: Black
authors.forename: Jerry
authors.initials: J
authors.lastname: Skotnicki
authors.forename: Jay
authors.initials: J
authors.lastname: Gibbons
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Philip
authors.initials: P
authors.lastname: Frost
authors.forename: Glenn
authors.initials: G
authors.lastname: Larsen
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C484302:apratastat; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse