Abstract
Tumor necrosis factor (TNF)-α is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF-α is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF-α-converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-α. TACE inhibitors that prevent the secretion of soluble TNF-α 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 IC50 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-α secretion at submicromolar concentrations, whereas there is no effect on the TNF-α mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF-α secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF-α 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.
Footnotes
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↵1 These authors contributed equally to this manuscript.
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DOI: 10.1124/jpet.103.059675.
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ABBREVIATIONS: RA, rheumatoid arthritis; TNF-α, tumor necrosis factor-α; MMP, matrix metalloproteinase; TACE, tumor necrosis factor-converting enzyme; TMI-1,4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)-thiomorpholinecarboxamide; OA, osteoarthritis; LPS, lipopolysaccharide; CIA, collagen-induced arthritis; FRET, fluorescence-based fluorescence resonance energy transfer; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; CFA, complete Freund's adjuvant; PD98059, 2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; CGS-27023, N-hydroxy-2(R)-(4-methoxysulfonyl) (3-picolyl)-(amino-3 methylbutaneamide hydrochloride monohydrate); BMS-275291, (S)-N-[2-mercapto-1-oxo-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)buty]-L-leucyl-N,3-dimethyl-L-valinamide; BAY 12-9566, 4-[4-(chlorophenyl)-phenyl]-4-oxo-2S-(phenylthiomethyl)butanoic acid.
- Received September 5, 2003.
- Accepted December 18, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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