Medical use of matrix metalloproteinase inhibitors for inhibitin

Details Medical use of matrix metalloproteinase inhibitors for inhibitin Medical use of matrix metalloproteinase inhibitors for inhibitin

1996-11-19

2000-07-25

Achutamurthy, Ponnathapura

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Monoclonal antibody or fragment thereof

4241301, 4241411, 514323, 514419, 514542, 514562, 514563, 514575, A61K 39395, A61K 31235

Patent

active

060933984

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to matrix metalloproteinase (MMP) inhibitors, especially collagenase inhibitors, and to their use in the manufacture of medicaments.
There are many different types of collagen found in the body and they, together with other extracellular matrix components, for example, elastin, gelatin, proteoglycan and fibronectin, make up a large proportion of the body's extracellular tissue. Matrix metalloproteinases (MMPs) are enzymes that are involved in the degradation and denaturation of extracellular matrix components. Collagenases, for example, are matrix metalloproteinases that degrade or denature collagen.
A large number of different collagenases are known to exist. These include interstitial collagenases, type IV-specific collagenases and collagenolytic proteinases. Collagenases are generally specific for collagens which, in their full triple helix structure, are extremely resistant to other enzymes.
Other MMPs are involved in the degradation and denaturing of different extracellular matrix components, for example, elastin, gelatin and proteoglycan. Some MMPs are able to degrade or denature several different types of collagen and also other extracellular matrix components. For example, stromelysin degrades type IV collagen, which is found in basement membrane, and also has an effect on other extracellular matrix components such as elastin, fibronectin and cartilage proteoglycans.
There is a classification system for MMPs, see Nagase et al 1992. For example, MMP1 is a collagenase that is sometimes called "collagenase", MMP2 is a 72 kD gelatinase, MMP3 is stromelysin and MMP9 is a 92 kD gelatinase. The official designations are used herein.
Collagenases have been implicated in a number of diseases, for example, rheumatoid arthritis [Mullins, D. E. et al 1983], periodontal disease and epidermolysis bullosa, and it has been proposed to use MMP inhibitors in the treatment of such conditions.
U.S. Pat. No. 5,183,900, No. 5,189,178 and No. 5,114,953 describe the synthesis of N-[2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide, also known as GM6001, Galardin or Galardin-MPI (trade names), and other MMP inhibitors, and their use in the prevention and treatment of corneal ulceration. Treatment of corneal ulcers with peptide hydroxamic acid inhibitors has been found to assist in the healing of those ulcers. Further details of such uses are given in Schultz et al 1992.
Also described in the above-mentioned US patent specifications is the use of collagenase inhibitors in situations where bacterial enzymes may be detrimental to tissue, for example, in bacterial ulceration.
Other collagenase inhibitors based on hydroxamic acid are disclosed in WO 90/05716, WO 90/05719 and WO 92/13831. Such collagenase inhibitors are disclosed as being used in the management of disease involving tissue degradation, particularly disease involving collagen breakdown, and/or the promotion of wound healing.
Other synthetic MMP inhibitors and, in particular, collagenase inhibitors that have been developed include those described in EP-A-126,974 and EP-A-159,396 and in U.S. Pat. Nos. 4,599,361 and 4,743,587.
One inhibitor undergoing clinical trials is BB-94 also known as Batimastat (British Bio-technology Ltd.). Potential uses of BB-94 for the control of cancer metatasis are described in EP-A-276436. It has been proposed to use an oral formulation of BB-94 in the treatment of bone cancer.
The present invention is concerned with the contraction of tissues, for example, scars. Contraction of tissues comprising extracellular matrix components, especially of collagen-comprising tissues, may occur in connection with many different pathological conditions and with surgical or cosmetic procedures. Contracture, for example, of scars, may cause physical problems, which may lead to the need for medical treatment, or it may cause problems of a purely cosmetic nature.
It has been proposed that contraction is cell-mediated and a number of studies have suggested possible mechanisms for cell mediated coll

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