Protein tyrosine kinase inhibitors for treating osteoarthritis

Details Protein tyrosine kinase inhibitors for treating osteoarthritis Protein tyrosine kinase inhibitors for treating osteoarthritis

1998-03-10

2003-04-22

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S520000, C514S523000

Reexamination Certificate

active

06552066

ABSTRACT:

BACKGROUND
Osteoarthritis or degenerative joint disease is a slowly progressive, irreversible, often monoarticular disease characterized by pain and loss of function (Mankin and Brandt, Pathogenesis of Osteoarthritis in “Textbook of Rheumatology”, Kelly, et al., (eds.) 3rd edition, W. B. Saunders Co., Philadelphia, pp.14699-111471) and Dean,
Arth. Rheum
. 20 (Suppl. 2):2 (1991)). The underlying cause of the pain and debilitation is the cartilage degradation that occurs as a result of the disease. A typical end-stage clinical picture includes complete erosion of the weight-bearing articular cartilage, requiring total joint replacement.
A class of inhibitors of protein kinase C are hymenialdisines and hymenialdisine analogues (Nambi et al., WO 93/16703). For example, debromohymenialdisine, inhibits protein kinase C gamma (108% at 100 &mgr;m), protein kinase C alpha (97% at 100 &mgr;m), protein kinase C beta (95% at 100 &mgr;m), as well as Ca
2+
-calmodulin dependent protein kinase II, (94% a 100 &mgr;m). Hymenialdisine and hymenialdisine analogues contain a pyrroloazepine ring system, shown below, along with a numbering system for the ring atoms:
Analogues of hymenialdisine also have a five membered, nitrogen-containing heterocyclic ring which is bonded to the four position of the pyrroloazepine ring system. Examples of hymenialdisines and analogues thereof which have been shown to inhibit cartilage degradation in the bovine cartilage explant assay include Z-debromohymenialdisine, E-debromohymenialdisine and Z-hymenialdisine (
Experientia
., 44:86 (1988) and Pettit, et al.,
Can. J. Chem
., 68:1621 (990).
Z-hymenialdisine or Z-debromohymenialdisine are represented by the formula:
Z-debromohymenialdisine also slows the progression of osteoarthritis in animals. The use of hymenialdisines and analogues thereof for the treatment of osteoarthritis is disclosed in Chipman and Faulkner, U.S. Ser. No. 08/472,902 filed Jun. 7, 1995, now U.S. Pat. No. 5,591,740, issued on Jan. 7, 1997, the entire teachings of which are incorporated herein by reference.
Currently, other than the hymenialdisines and analogues thereof, discussed above, there is no known, demonstrated therapeutic approach available that will slow the clinical progression of osteoarthritis, although steroids and non-steroidal anti-inflammatory drugs are used to ameliorate the pain and inflammation associated with the disease. Consequently, there is a need for new therapeutics which slow the joint degeneration caused by osteoarthritis.
SUMMARY OF THE INVENTION
It has now been found that tyrosine kinase inhibitors significantly reduce or prevent cartilage degradation in chondrocytes. Specifically, the tyrosine kinase inhibitors genistein, herbimycin A, 4,5-dianilinophthalimide (DAPH), tyrphostin AG 82 and tyrphostin AG 556 slow interleukin-1 (IL-1) induced degradation of extracellular matrix by chondrocytes in cell culture (Examples 1 and 7). Herbimycin A and tyrphostin AG 82 also reduce cartilage degradation in a bovine cartilage explant assay (Examples 2 and 3). Protein tyrosine kinase inhibitors have also been shown to inhibit IL-1 induced increases in stromelysin mRNA levels (Example 4) and IL-1 induced increases in prostromelysin protein levels (Example 5). Based on these discoveries, methods of treating individuals with osteoarthritis and methods of inhibiting cartilage degradation in individuals are disclosed.
One embodiment of the present invention is a method of treating an individual or animal with osteoarthritis. The method comprises administering a therapeutically effective amount of a protein tyrosine kinase inhibitor to the individual or animal. Another embodiment of the present invention is a method of inhibiting or preventing cartilage degradation in an individual or animal. The method comprises administering a therapeutically effective amount of a tyrosine kinase inhibitor to the individual or animal.
The disclosed method of treatment inhibits the cartilage degradation associated with the osteoarthritis. Treatments presently used for osteoarthritis only alleviate the symptoms of the disease, for example the pain and inflammation that result from joint deterioration. Therefore, the disclosed treatment for osteoarthritis has the advantage over presently used methods of treatment in that the disclosed method can slow or arrest the progression of the disease rather than merely alleviate its symptoms.
DETAILED DESCRIPTION OF THE INVENTION
Protein tyrosine kinases (PTKs) occur as membrane-bound receptors or cytoplasmic proteins. They are involved in regulating a wide variety of cellular functions, including cytokine responses, antigen-dependent immune responses, cellular transformation by RNA viruses, oncogenesis, cell cycle, and modification of cell morphology. PTKs regulate these functions by activating, directly or indirectly, intracellular signalling pathways, including Ras, phosphatidylinositol 3 kinase (PI3K), phospholipase C-&ggr; (PLC-&ggr;) and mitogen-activated pathway (MAP). It has now been found that PTKs also regulate cellular functions which result in the cartilage degradation associated with osteoarthritis.
Activation of PTKs results in auto-phosphorylation of a tyrosine residue in the protein tyrosine kinase. Auto-phosphorylation of PTKs facilitates the interaction of protein substrates with the active site and results in the phosphorylation of tyrosine residues in the protein substrates. Protein substrates of PTKs are generally cytosolic signalling molecules whose function is turned off or on as a result of phosphorylation. Activation of protein substrates by PTKs can cause a cascade of intracellular reactions resulting in the activation of other proteins or previously unexpressed or underexpressed genes. This cascade of events is referred to as a signalling pathway, which regulates cellular functions, including the cellular functions discussed above.
Because PTKs regulate cellular functions which cause the cartilage degradation associated which osteoarthritis, the progression of the disease can be slowed or arrested by inhibiting PTKs. As used herein, “inhibiting a PTK” refers to blocking the signal transduction pathway whereby an activated PTK regulates a cellular function. In the present invention, a PTK inhibitor is used which blocks a signal transduction pathway in which an activated PTK regulates one or more cellular functions which result in cartilage degradation. Included are PTK inhibitors which reduce cartilage degradation in IL-1 activated chondrocytes in cell culture, which downregulate matrix metalloproteinase (MMP) and/or aggrecanase mRNA levels in IL-1 activated chondrocytes in cell culture or which downregulate MMP and/or aggrecanase protein levels in chondrocytes in cell culture.
A PTK inhibitor includes a small organic molecule or polypeptide which blocks a PTK regulated signaling pathway, as discussed above. As used herein, a PTK inhibitor can act by a number of different mechanisms. Preferably, the PTK inhibitor can act by inhibiting the initial autophosphorylation event, discussed above. Alternatively, the PTK inhibitor can act by inhibiting the phosphorylation of the protein substrate, for example, by competing with the protein substrate or ATP for binding with the PTK. A PTK can also act by more than one of these mechanisms.
As used herein, a PTK inhibitor can act by other mechanisms. For example, compounds which prevent binding of activating molecules (e.g. growth factors) to receptor PTKs, either by blocking the receptor (e.g. a receptor antagonist) or by binding with the activating molecule itself. Alternatively, a PTK inhibitor can act by blocking one of the biochemical reactions in the cascade of reactions initiated by activation of the PTK. For example, as noted above, activation of a PTK can result in the activation of the Ras, phosphatidylinositol 3 kinase (PI3K), phospholipase C-&ggr; (PLC&ggr;) and mitogen-activated pathway (MAP). Agents which can block any one of these pathways following their initiation by PTK activation can also downregulate cellular functi

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