TY - JOUR T1 - Identification and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-<em>N</em>-hydroxy-2,2-dimethyl-(3<em>S</em>)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 348 LP - 355 DO - 10.1124/jpet.103.059675 VL - 309 IS - 1 AU - Yuhua Zhang AU - Jun Xu AU - Jeremy Levin AU - Martin Hegen AU - Guangde Li AU - Heidi Robertshaw AU - Fionula Brennan AU - Terri Cummons AU - Dave Clarke AU - Nichole Vansell AU - Cheryl Nickerson-Nutter AU - Dauphine Barone AU - Ken Mohler AU - Roy Black AU - Jerry Skotnicki AU - Jay Gibbons AU - Marc Feldmann AU - Philip Frost AU - Glenn Larsen AU - Lih-Ling Lin Y1 - 2004/04/01 UR - http://jpet.aspetjournals.org/content/309/1/348.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -