WO1997017088A1 - Inhibiteurs de metalloproteinase matricielle et leur utilisation therapeutique - Google Patents
Inhibiteurs de metalloproteinase matricielle et leur utilisation therapeutique Download PDFInfo
- Publication number
- WO1997017088A1 WO1997017088A1 PCT/GB1996/002746 GB9602746W WO9717088A1 WO 1997017088 A1 WO1997017088 A1 WO 1997017088A1 GB 9602746 W GB9602746 W GB 9602746W WO 9717088 A1 WO9717088 A1 WO 9717088A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- inhibitor
- matrix metalloproteinase
- treatment
- tnfα
- use according
- Prior art date
Links
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 title claims abstract description 5
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 title claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims abstract description 11
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- 108050007852 Tumour necrosis factor Proteins 0.000 claims abstract description 4
- 102000018594 Tumour necrosis factor Human genes 0.000 claims abstract description 4
- 230000001747 exhibiting effect Effects 0.000 claims abstract 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 12
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 12
- 108010002352 Interleukin-1 Proteins 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 16
- 230000000694 effects Effects 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 3
- 229940124761 MMP inhibitor Drugs 0.000 description 2
- 206010067268 Post procedural infection Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 206010011409 Cross infection Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
Definitions
- This invention relates to the therapeutic use of compounds that inhibit matrix metalloproteinases.
- MMP matrix metalloproteinases
- TNF ⁇ tumour necrosis factor
- Various effects of these inhibitory activities are described, as are suitable formulations and dosages.
- TNF ⁇ and IL-13 in the body, so that a partial reduction in both of these may well have a larger effect clinically than a total reduction in just one of them (that is TNF ⁇ ) .
- TNF ⁇ a total reduction in just one of them
- a complete reduction in TNF ⁇ levels may be detrimental.
- the combined partial inhibition of these two cytokines should overcome this detrimental influence and yet provide as good if not better efficacy.
- y TNF ⁇ Inhibition, in terms of IC 50 according to Example D of Application No. PCT/GB96/01136.
- z IL-1 Inhibition, in terms of Example D of Application No. PCT/GB96/01136, modified by using a commercially-available IL-l3 kit (R & D Systems) to assay the supernatant for IL-13, determining the activity in the presence of 1 mM inhibitor or dilutions thereof by comparison to activity in a control devoid of inhibitor, and reporting IC 50 as that inhibitor concentration effecting 50% inhibition of the production of IL-13.
- x is below IO *4 M, preferably below 10 * M, more preferably 10 M to 10 M.
- y is below 10 *4 H, preferably 10 * M to 10 * M, more preferably 5 x 10 *5 M to IO *6 M.
- z is below l ⁇ "4 M, preferably 10 * M to 10 * M, more preferably 5 x IO *5 M to IO *6 M.
- Compounds as defined above may be used in a method of treatment (which term includes prevention and prophylaxis) of the animal, and especially human, body, in post- operative care (whether in or out of hospital) .
- the treatment regime may be a continuation of that given before the operation, e.g. for arthritis, asthma, cancer or any other condition susceptible to treatment with a MMP inhibitor. They may also be used where the subject is susceptible to the recurrence of lymphoma.
- Description of the Invention Compounds that meet the criteria given above are described in the specifications identified above. Specific examples of such compounds are given in the Table, below.
- Reduction of the potential side-effects of cancer or infection may be particularly beneficial following surgery.
- post-operative infection in patients undergoing operation for cancer removal or, for example, hip or other joint replacement may be treated.
- Treatment is enhanced in situations where the potential enhancement in susceptibility to infection due to TNF reduction is coincident with the treatment of the disease.
- a suitable MMP inhibitor may be used to treat cancer patients concomitant with surgery, where that treatment may give rise to an increased tendency to post-operative infection, such as a nosocomial infection.
- such a compound may be used during and after hip replacement and for the treatment of rheumatoid arthritis or osteoarthritis.
- TNF and optionally also of IL-1 rather than total TNF inhibition coincident with MMP inhibition is intended to give a benefit in reducing potential side-effects that the surgery had made the patient prone to.
- the compounds defined herein are of benefit in reducing the occurrence of lymphoma.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
On utilise un inhibiteur de métalloprotéinase matricielle dans le traitement d'un sujet sensible à un état pouvant être traité à l'aide de cet inhibiteur, ou présentant un tel état. On conduit ce traitement après une opération chirurgicale pratiquée sur ce sujet et l'inhibiteur, d'une part, démontre un IC50 inférieur à 100 νM par rapport à la métalloprotéinase matricielle et, d'autre part, ne provoque pas de diminution des concentrations du facteur de nécrose tumorale ou provoque une diminution partielle de celles-ci.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU75026/96A AU7502696A (en) | 1995-11-10 | 1996-11-08 | Matrix metalloproteinase inhibitors and their therapeutic use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9523066.0A GB9523066D0 (en) | 1995-11-10 | 1995-11-10 | Compounds and their therapeutic use |
| GB9523066.0 | 1995-11-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997017088A1 true WO1997017088A1 (fr) | 1997-05-15 |
Family
ID=10783708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1996/002746 WO1997017088A1 (fr) | 1995-11-10 | 1996-11-08 | Inhibiteurs de metalloproteinase matricielle et leur utilisation therapeutique |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7502696A (fr) |
| GB (1) | GB9523066D0 (fr) |
| WO (1) | WO1997017088A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039024A1 (fr) * | 1997-03-03 | 1998-09-11 | Darwin Discovery Limited | Inhibiteurs selectifs de la metalloprotease matricielle presentant des effets secondaires reduits |
| US6953788B1 (en) | 1996-09-19 | 2005-10-11 | Aventis Pharmaceuticals Inc. | 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995013289A1 (fr) * | 1993-11-10 | 1995-05-18 | Chiroscience Limited | Composes peptidyles et leur utilisation therapeutique en tant qu'inhibiteurs des metalloproteases |
| WO1996011209A1 (fr) * | 1994-10-05 | 1996-04-18 | Chiroscience Limited | Composes de peptidyle et leur usage therapeutique en tant qu'inhibiteurs des metalloproteases |
| WO1996035711A1 (fr) * | 1995-05-10 | 1996-11-14 | Chiroscience Limited | Composes peptidiques inhibant la liberation de la metalloproteinase et du tnf, et leur utilisation therapeutique |
-
1995
- 1995-11-10 GB GBGB9523066.0A patent/GB9523066D0/en active Pending
-
1996
- 1996-11-08 WO PCT/GB1996/002746 patent/WO1997017088A1/fr active Application Filing
- 1996-11-08 AU AU75026/96A patent/AU7502696A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995013289A1 (fr) * | 1993-11-10 | 1995-05-18 | Chiroscience Limited | Composes peptidyles et leur utilisation therapeutique en tant qu'inhibiteurs des metalloproteases |
| WO1996011209A1 (fr) * | 1994-10-05 | 1996-04-18 | Chiroscience Limited | Composes de peptidyle et leur usage therapeutique en tant qu'inhibiteurs des metalloproteases |
| WO1996035711A1 (fr) * | 1995-05-10 | 1996-11-14 | Chiroscience Limited | Composes peptidiques inhibant la liberation de la metalloproteinase et du tnf, et leur utilisation therapeutique |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6953788B1 (en) | 1996-09-19 | 2005-10-11 | Aventis Pharmaceuticals Inc. | 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase |
| WO1998039024A1 (fr) * | 1997-03-03 | 1998-09-11 | Darwin Discovery Limited | Inhibiteurs selectifs de la metalloprotease matricielle presentant des effets secondaires reduits |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9523066D0 (en) | 1996-01-10 |
| AU7502696A (en) | 1997-05-29 |
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