Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-05-27
2001-09-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S477000, C548S451000, C548S183000, C548S319500, C548S317500, C548S550000, C548S547000, C548S263400, C548S226000, C548S510000, C548S573000, C548S210000, C548S221000, C548S309700, C548S361500, C548S207000, C548S479000, C562S621000, C568S042000, C568S325000
Reexamination Certificate
active
06288063
ABSTRACT:
FIELD
This invention relates to enzyme inhibitors, and more particularly, to novel matrix metalloprotease-inhibiting 4-Biarylbutyrohydroxamic Acids, 5-Biarylpentanohydroxamic Acids, 5-Biaryl-1-hydroxy-2-pentanones, 6-Biaryl-1-hydroxy-2-hexanones, N-(4-Biarylbutyryl)sulfonamides and N-(5-Biarylpentanoyl)sulfonamides and derivatives thereof.
BACKGROUND
The matrix metalloproteases (aka. matrix metalloendo-proteinases or MMPs) are a family of zinc endoproteinases which include, but are not limited to, interstitial collagenase (aka. MMP-1), stromelysin (aka. proteoglycanase, transin, or MMP-3), gelatinase A (aka. 72 kDa-gelatinase or MMP-2) and gelatinase B (aka. 95 kDa-gelatinase or MMP-9). These MMPs are secreted by a variety of cells including fibroblasts and chondrocytes, along with natural proteinatious inhibitors known as TIMPs (Tissue Inhibitor of MetalloProteinase).
All of these MMPs are capable of destroying a variety of connective tissue components of articular cartilage or basement membranes. Each MMP is secreted as an inactive proenzyme which must be cleaved in a subsequent step before it is able to exert its own proteolytic activity. In addition to the matrix destroying effect, certain of these MMPs such as MMP-3 have been implemented as the in vivo activator for other MMPs such as MMP-1 and MMP-9 (A. Ho, H. Nagase, Arch Biochem Biophys., 267, 211-16 (1988); Y. Ogata, J. J. Enghild, H. Nagase, J. Biol. Chem., 267, 3581-84 (1992)). Thus, a cascade of proteolytic activity can be initiated by an excess of MMP-3. It follows that specific MMP-3 inhibitors should limit the activity of other MMPs that are not directly inhibited by such inhibitors.
It has also been reported that MMP-3 can cleave and thereby inactivate the endogenous inhibitors of other proteinases such as elastase (P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell G., Murphy, FEBS Letts., 279, 1, 91-94 (1991)). Inhibitors of MMP-3 could thus influence the activity of other destructive proteinases by modifying the level of their endogenous inhibitors.
MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteases such as the adamalysin family (or ADAMs) whose members include TNF&agr; converting enzyme (TACE) and ADAM-10, which can cause the release of TNF from cells.
A number of diseases or conditions are thought to be mediated by excess or undesired matrix-destroying metalloprotease activity or by an imbalance in the ratio of the MMPs to the TIMPs or through the action of the release of TNF. These include: a) osteoarthritis (Woessner, et al.,
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Brittelli David Ross
Ha Sookhee Nicole
Kluender Harold Clinton Eugene
Schoen William Riley
Bayer Corporation
Rao Deepak R.
Shah Mukund J.
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