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INFLAMMATION AND IMMUNOPHARMACOLOGY

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--Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis

Wyeth Research, Cambridge, Massachusetts (Y.Z., M.H., Gu.L., C.N.-N., Gl.L., L.-L.L.); Wyeth Research, Pearl River, New York (J.X., J.L., T.C., D.C., N.V., J.S., J.G., P.F.); Amgen Inc., Seattle, Washington (D.B., K.M., R.B.); and The Kennedy Institute of Rheumatology Division, Imperial College, London, United Kingdom (H.R., F.B., M.F.)

Tumor necrosis factor (TNF)- is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF- is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF--converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-. TACE inhibitors that prevent the secretion of soluble TNF- 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- secretion at submicromolar concentrations, whereas there is no effect on the TNF- mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF- secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF- 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.

Address correspondence to: Dr. Yuhua Zhang, Wyeth Research, 200 Cambridge Park Dr., Cambridge, MA 02140. E-mail: yzhang{at}wyeth.com

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