Metalloproteinase inhibitors

Details Metalloproteinase inhibitors Metalloproteinase inhibitors

1998-04-22

2000-08-15

Seaman, D. Margaret

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514352, 514371, 514372, 514620, 546163, 546309, 548190, 548214, 165153, A61K 3144, C07D21538, C07D21372, C07D27704, C07C23300

Patent

active

061037397

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to therapeutically active pseudopeptide or peptidyl compounds, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation.


BACKGROUND TO THE INVENTION

The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72 kDa gelatinase, 92 kDa gelatinase, stromelysin-1, stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor a (TNF-.alpha.). Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs. MMPs can attack the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF-.alpha. to release soluble TNF-.alpha.. MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. Chapman et al (J. Med. Chem. 1993, 36, 4293-4301) report some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the active site zinc (II) ion in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, mercapto, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
Gray et. al., Biochemical and Biophysical Research Communication, Vol. 101, No. 4, 1981 discloses collagense inhibitors which are .alpha.-mercaptoamides of tetrapeptides, in which the mercapto group functions as the zinc binding group. The patent publications WO 95/13289 and WO 96/11209 disclose a class of MMP inhibitors in which the zinc binding group is again an .alpha.-mercaptoamide group. MMP inhibitors having an N-formyl-N-hydroxyamino zinc binding group are also known, eg from EP-A-0236872.


BRIEF DESCRIPTION OF THE INVENTION

The present invention makes available a new class of MMP inhibitors having as zinc binding groups (i) .alpha.-mercaptoamide groups analogous to those of Gray et. al, WO 95/13289 and WO 96/11209 or (ii) an N-formyl-N-hydroxyamino group. The compounds of the invention are principally distinguished from the compounds disclosed in WO 95/13289 and WO 96/11209, and from known MMP inhibitors having the N-formyl-N-hydroxyamino zinc binding group, by having a terminal arylamide or heteroarylamide group. The

REFERENCES:
Hansen, J Nucl Med, 35 (7), pp. 1198-1205, 1994.
Hansen, Inorg Chem, 31(3), pp. 2801-2808, 1992.
CA 123:314549, Montana, 1995.

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