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.
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.
Zhang
Yuhua
Y
Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. yzhang@wyeth.com
Xu
Jun
J
Levin
Jeremy
J
Hegen
Martin
M
Li
Guangde
G
Robertshaw
Heidi
H
Brennan
Fionula
F
Cummons
Terri
T
Clarke
Dave
D
Vansell
Nichole
N
Nickerson-Nutter
Cheryl
C
Barone
Dauphine
D
Mohler
Ken
K
Black
Roy
R
Skotnicki
Jerry
J
Gibbons
Jay
J
Feldmann
Marc
M
Frost
Philip
P
Larsen
Glenn
G
Lin
Lih-Ling
LL
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
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