Inhibition of TNF production with matrix metaloproteinase inhibi

Details Inhibition of TNF production with matrix metaloproteinase inhibi Inhibition of TNF production with matrix metaloproteinase inhibi

1995-05-12

1997-11-25

Jarvis, William R. A.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

A61K 3119

Patent

active

056913826

DESCRIPTION:

BRIEF SUMMARY
This application claims priority to PCT/GB93/02331 filed Nov. 12, 1993, published as WO94/10990 May 26, 1994, published as WO94/10990 May 26, 1994.
This invention relates to a new pharmaceutical and veterinary use of certain hydroxamic acid derivatives, previously known in the art as inhibitors of matrix metalloproteinases such as collagenase. In accordance with the invention the known compounds have been found to be capable of inhibiting the production of tumour necrosis factor (TNF) by cells, and thus to be useful in the management of diseases or conditions mediated by overproduction of, or over-responsiveness to, TNF.


BACKGROUND OF THE INVENTION

TNF is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form (Jue, D-M et al., (1990) Biochemistry 29:8371-8377), which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Preventing the production or action of TNF is, therefore, predicted to be a potent therapeutic strategy for many inflammatory, infectious, immunological or malignant diseases.
It has been shown that the effects of TNF are mediated by two peptides, TNF .alpha. and TNF .beta.. Although these peptides have only 30% homology with each other, they activate the same receptors and are encoded by immediately adjacent genes. As used herein, the term tumour necrosis factor or TNF therefore means tumour necrosis factor .alpha. and peptides having a high degree of sequence homology with, and substantially similar physiological effects to, TNF .alpha., for example TNF .beta..
It is known that metalloproteinases such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are involved in connective tissue breakdown. The known hydroxamic acid-based MMP inhibitors with which this invention is concerned are those forming part of the state of the art by virtue of any of the following patent publications:


______________________________________ US 4599361 ("Searle") EP-A-0236872 ("Roche 1") EP-A-0274453 ("Bellon") WO 90/05716 (British Biotechnology) ("BBL1") WO 90/05719 (British Biotechnology) ("BBL2") WO 91/02716 (British Biotechnology) ("BBL3") EP-A-0489577 ("Celltech 1") EP-A-0489579 ("Celltech 2") EP-A-0497192 ("Roche 2") WO 92/13831 (British Biotechnology) ("BBL4") WO 92/22523 (Research Corporation Technologies) ("RCT") WO 93/09090 ("Yamanouchi") WO 93/09097 ("Sankyo") ______________________________________ reference, and the reader is referred thereto for details of the structures of the compounds disclosed and methods for their preparation. The MMP inhibiting hydroxamic acid derivatives disclosed therein can be regarded as having the following basic structure (I): ##STR1## wherein the five substituents R.sub.1 -R.sub.5 may vary according to the detailed disclosure of each publication. However, neither the compounds per se nor the method of their preparation form part of this invention. Rather, the invention arises from the finding by the present inventors that representative members of the compound classes disclosed in each of those publications have the property of inhibiting release of TNF from cells, and the realisation that such activity is widespread amongst the disclosed compounds.
Without prejudice to the true disclosures of the patent

REFERENCES:
patent: 4599361 (1986-07-01), Fukami et al.

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