Matrix metalloprotease inhibitors

Details Matrix metalloprotease inhibitors Matrix metalloprotease inhibitors

2000-04-11

2002-02-26

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Hydroxamic acids, chalcogen analogs or salts thereof

C564S153000, C514S357000, C514S399000, C514S419000, C514S438000, C514S520000, C514S524000, C514S563000, C514S575000, C546S337000, C548S304400, C548S495000, C549S076000, C549S077000, C549S296000, C558S414000, C562S448000

Reexamination Certificate

active

06350907

ABSTRACT:

This invention relates to certain compounds, and their pharmaceutically acceptable salts, which inhibit matrix metalloproteases (MMPs), particularly MMP-3, MMP-12 and MMP-13. They are therefore useful in the treatment of mammals having conditions alleviable by inhibition of MMPs, especially MMP-3, MMP-12 and MMP-13.
MMPs constitute a family of structurally similar zinc-containing metalloproteases, which are involved in the remodelling, repair and degradation of extracellular matrix proteins, both as part of normal physiological processes and in pathological conditions. Since they have high destructive potential, the MMPs are usually under close regulation, and failure to maintain MMP regulation has been implicated as a component of a number of conditions. Examples of conditions where MMPs are thought to be important are those involving bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling during wound repair and organ differentiation such as such as in venous and diabetic ulcers, pressure sores, colon ulcers for example ulcerative colitis and Crohn's disease, duodenal ulcers, fibrosis, local invasion of tumours into adjacent areas, metastatic spread of tumour cells from primary to secondary sites, and tissue destruction in arthritis, skin disorders such as dystrophic epidermolysis bulosa, dermatitis herpetiformis, or conditions caused by or complicated by embolic phenomena, such as chronic or acute cardiac or cerebral infarctions.
Conditions where MMP-3 and MMP-13 have been implicated include tissue destruction such as in venous and diabetic ulcers, pressure sores, colon ulcers for example ulcerative colitis and Crohn's disease, duodenal ulcers, and tissue destruction in arthritis, skin disorders such as dystrophic epidermolysis bulosa, dermatitis herpetiformis, or conditions caused by or complicated by embolic phenomena, such as chronic or acute cardiac or cerebral infarctions.
Another important function of certain MMPs is to activate other enzymes, including other MMPs, by cleaving the pro-domain from their protease domain. Thus, certain MMPs act to regulate the activities of other MMPs, so that over-production in one MMP may lead to excessive proteolysis of extracellular matrix by another.
Excessive production of MMP-3 is thought to be responsible for pathological tissue breakdown which underlies a number of diseases and conditions. For example, MMP-3 has been found in the synovium and cartilage of osteoarthritis and rheumatoid arthritis patients, thus implicating MMP-3 in the joint damage caused by these diseases. (See K. L. Sirum, C. E Brinkerhoff,
Biochemistry,
1989, 28, 8691; Z. Gunja-Smith, H. Nagasse, J. F. Woessner,
Biochem. J.,
1989, 258, 115). MMP-13 is also thought to play an important role in the pathology of osteoarthritis and rheumatoid arthritis (M. Stahle-Backdahle, B. Sandstedt, K. Bruce, A. Lindahl, M. G. Jimenez, J. A. Vega, C. Lopez Otin,
Lab. Invest.,
1997, 76, 717-28; O. Lindy, Y. T. Konttinen, T. Sorsa, Y. Ding, S. Santavirta, A. Ceponis, C. Lopez Otin,
Arthritis Rheum.
1997, 40, 1391-9).
Over-expression of MMP-3 is also thought to be responsible for much of the tissue damage and chronicity of chronic wounds, such as venous and diabetic ulcers, and pressure sores. (See M. Vaalamo, M. Weckroth, P. Puoakkainen, J. Kere, P. Saarinen, J. Lauharanta, U. K. Saarialho-Kere,
Brit. J Dermatology,
1996, 135, 52-59).
During the healing of normal and chronic wounds, MMP-1 is expressed by migrating keratinocytes at the wound edges (U. K. Saarialho-Kere, S. O. Kovacs, A. P. Pentland,
J Clin. Invest.
1993, 92, 2858-66). There is evidence which suggests MMP-1 is required for keratinocyte migration on a collagen type I matrix in vitro, and is completely inhibited by the presence of the non-selective MMP inhibitor SC44463 ((N4-hydroxy)-N1-[(1S)-2-(4-methoxyphenyl)methyl-1-((1R)-methylamino)carbonyl)]-(2R)-2-(2-methylpropyl)butanediamide) (B. K. Pilcher, J. A. Dumin, B. D. Sudbeck, S. M. Krane, H. G. Welgus, W.C. Parks,
J. Cell Biol.,
1997, 137, 1-13). Keratinocyte migration in vivo is essential for effective wound healing to occur.
MMP-2 and MMP-9 appear to play important roles in wound healing during the extended remodelling phase and the onset of re-epithelialisation, respectively (M. S. Agren,
Brit. J. Dermatology,
1994, 131, 634-40; T. Salo, M. Mäkänen, M. Kylmäniemi,
Lab. Invest.,
1994, 70, 176-82). The potent, non-selective MMP inhibitor BB94 ((2S,3R)-5-methyl-3-{[(1S)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl}-2-[(2-thienylthio)methyl]hexanohydroxamic acid, batimastat), inhibits endothelial cell invasion of basement membrane, thereby inhibiting angiogenesis (G. Tarboletti, A. Garofalo, D. Belotti, T. Drudis, P. Borsotti, E. Scanziani, P. D. Brown, R. Giavazzi,
J. Natl. Cancer Inst.,
1995, 87, 293-8). There is evidence that this process requires active MMP-2 and/or 9.
Thus, non-selective MMP inhibitors which inhibit MMPs 1 and/or 2 and/or 9 would be expected to impair wound healing. As described above, MNP-14 is responsible for the activation of MMP-2, and thus inhibition of MMP-14 might also result in impaired wound healing.
The production of MMP-3 has also been thought to be involved in tissue damage in conditions where there is ulceration of the colon (as in ulcerative colitis and Crohn's disease, see S. L. Pender, S. P. Tickle, A. J. Docherty, D. Howie, N. C. Wathen, T. T. MacDonald,
J. Immunol.,
1997, 158, 1582; C. J. Bailey, R. M. Hembry, A. Alexander, M. H. Irving, M. E. Grant, C. A. Shuttleworth,
J. Clin. Pathol.,
1994, 47, 113-6), or duodenum (see U. K. Saarialho-Kere, M. Vaalamo, P. Puolakkainen, K. Airola, W. C. Parks, M. L. Kaajalainen-Lindsberg,
Am. J. Pathol.,
1996, 148, 519-26). It is also likely that MMP-1 and MMP-2 are required during the healing phase of these conditions. A selective MMP-3 inhibitor would be more effective than a non-selective inhibitor.
MMP-3 has also been implicated in skin diseases such as dystrophic epidermolysis bullosa (T. Sato, K. Nomura, I. Hashimoto,
Arch. Dermatol. Res.,
1995, 287, 428) and dermatitis herpetiformis (K. Airola, M. Vaalamo, T. Reunala, U. K. Saarialho-Kere,
J. Invest. Dermatology,
1995, 105, 184-9).
Rupture of atherosclerotic plaques by MMP-3 can lead to cardiac or cerebral infarction. (F. Mach, et al.,
Circulation,
1997, 96, 396-9.) Thus, MMP-3 inhibitors may find utility in the treatment of conditions caused by or complicated by embolic phenomena, such as chronic or acute cardiac or cerebral infarctions. MMP-12 (macrophage elastase) is thought to contribute to the pathology of atherosclerosis, gastro-intestinal ulcers and emphysema. For example, in a rabbit model of developing atherosclerosis, MMP-12 is expressed abundantly by macrophage foam cells (S. Matsumoto, et al,
Am.J.Pathol.
1998, 153, 109). MMP-12 is also expressed abundantly by macrophages in the vicinity of shedding mucosal epithelium in human gastro-intestinal ulcers, such as those found in patients with ulcerative colitis and Crohn's disease (M. Vaalamo, et al,
Am.J.Pathol.
, 1998, 152, 1005). MMP-12 is thought to be important for the progression of lung damage by cigarette smoke. In a model of cigarette smoke-induced emphysema, mice lacking the gene for MMP-12 were resistant to developing the condition whereas wild-typemice suffered significant lung damage (R D Hautamaki, et al,
Science,
1997, 277, 2002).
For recent reviews of MMPs, see Zask et al,
Current Pharmaceutical Design,
1996, 2, 624-661; Beckett,
Exp. Opin. Ther. Patents,
1996, 6, 1305-1315; and Beckett et al, Drug Discovery Today, vol 1(no.1), 1996, 16-26.
Alternative names for various MMPs and substrates acted on by these are shown in the table below (Zask et al, supra).
Enzyme
Other names
Preferred substrates
MMP-1
Collagenase-1, interstitial
Collagens I, II, III, VII, X, gelatins
collagenase
MMP-2
Gelatinase A, 72 kDa
Gelatins, collagens IV, V, VII, X,
gelatinase
elastin, fi

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