Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-30
2004-01-27
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S331000, C514S018700, C548S100000, C548S400000, C549S029000
Reexamination Certificate
active
06683055
ABSTRACT:
The present invention relates to peptide substances, their preparation and their use as complement inhibitors. In particular, these are substances having a guanidine or amidine radical as terminal group. In particular, the present invention relates to inhibitors of the complement proteases C1s and C1r.
The activation of the complement system leads, via a cascade of about 30 proteins, finally to, inter alia, the lysis of cells. At the same time, molecules which, like, for example, C5a, can lead to an inflammatory reaction are liberated. Under physiological conditions, the complement system provides defense against foreign bodies, e.g. viruses, fungi, bacteria and cancer cells. The activation by the various routes takes place initially via proteases. Activation enables these proteases to activate other molecules of the complement system, which in turn may be inactive proteases. Under physiological conditions, this system—similarly to blood coagulation—is under the control of regulator proteins which counteract excessive activation of the complement system. In these cases, intervention to inhibit the complement system is not advantageous.
In some cases, however, the complement system overreacts and this contributes to the pathophysiology of disorders. In these cases, therapeutic intervention in the complement system by inhibition or modulation of the overshooting reaction is desirable. Inhibition of the complement system is possible at various levels in the complement system and by inhibition of various effectors. The literature contains examples of the inhibition of the serine proteases at the C1 level with the aid of the C1-esterase inhibitor as well as inhibition at the level of the C3- and C5-convertases with the aid of soluble complement receptor CR1 (sCR1), inhibition at the C5 level with the aid of antibodies and inhibition at the C5a level with the aid of antibodies or antagonists. The tools used for achieving the inhibition in the abovementioned examples are proteins. The present invention describes low molecular weight substances which are used for inhibiting the complement system.
In general activation of the complement system is to be expected in every inflammatory disorder which is associated with intrusion of neutrophilic blood cells. It is therefore expected that an improvement in pathophysiological status will be achieved in all these disorders by inhibiting parts of the complement system.
The activation of the complement is associated with the following disorders or pathophysiological conditions (Liszewski, M. K.; Atkinson, J. P.: Exp. Opin. Invest. Drugs 7(3) (1998): 324-332; Morgan, B. P.: Biochemical Society Transactions 24; (1996), 224-9; Morgan, B. P.: Critical Review in Clinical Laboratory Sciences 32 (3); (1995), 265-298; Hagmann, W. K.; Sindelar, R. D.: Annual reports in medicinal chemistry 27, (1992), 199 et seq.; Lucchesi, B. R.; Kilgore, K. S.: Immunopharmacology 38 (1997), 27-42; Makrides, S. C.: Pharmacological Reviews 50(1)(1998), 59-85)
Reperfusion injuries after ischemias; ischemic conditions, during, for example, operations with the aid of heart-lung machines; operations in which blood vessels are clamped off generally for avoiding major hemorrhages; myocardial infarction; thromboembolic cerebral infarction; pulmonary thrombosis, etc.;
Hyperacute organ rejection; especially in xenotransplantations;
Organ failure, e.g. multiple organ failure or ARDS (adult respiratory distress syndrome);
Disorders due to trauma (cranial trauma) or multiple injury, e.g. thermal injury (burns);
Anaphylactic shock;
Sepsis; “vascular leak syndrome”: in the case of sepsis and after treatment with biological agents, such as interleukin-2 or after transplantation;
Alzheimer's disease and other inflammatory neurological disorders, such as myastenia graevis, multiple sclerosis, cerebral lupus, Guillain-Barre syndrome; meningitis; encephalitis;
Systemic lupus erythematosus (SLE);
Rheumatoid arthritis and other inflammatory disorders of the rheumatoid disorder group, e.g. Behcet's Syndrome; Juvenile rheumatoid arthritis;
Renal inflammations of various origin, e.g. Glomerulonephritis,
Lupus nephriti;
Pancreatitis;
Asthma; chronic bronchitis;
Complications during dialysis in the case of kidney failure;
Vasculitis; thyroiditis;
Ulcerative colitis
and other inflammatory disorders of the gastrointestinal tract;
Autoimmune diseases.
It is possible that complement plays a role in spontaneous abortions, based on immunological rejection reactions (Giacomucci E., Bulletti C., Polli V., Prefetto R A., Flamigni C., Immunologically mediated abortion (IMA). Journal of Steroid Biochemistry & Molecular Biology, 49(2-3) (1994), 107-21). Here, it is possible that modulation of the immunological rejection reaction is achieved by inhibition of the complement system and hence the rate of abortions is correspondingly reduced.
Complement activation plays a role in the case of side effects of drugs. Liposome-based therapies which are used, for example, in cancer treatment may be mentioned as an example here. Hypersensitive reactions have been observed in patients who have been treated with drug formulations based on liposomes (Transfusion 37 (1997) 150). Activation of the complement system has also been demonstrated for other excipients used in drug formulations, e.g. Cremophor EL (Szebeni, J. et al. Journal of the National Cancer Institute 90 (4); 1998). The complement activation may therefore be responsible for the anaphylactoid reactions observed in some cases. Inhibition of the complement system, for example by the C1s inhibitors mentioned here, should therefore alleviate the side effects of medicaments based on activation of the complement system and reduce resulting hypersensitivity reactions.
In the abovementioned disorders, activation of the complement system has been demonstrated.
The synthesis of complement proteins in special diseased tissues or organs indicates participation of the complement system in the pathophysiology of these disorders. Thus, in the case of myocardial infarction, vigorous further synthesis of many complement proteins in the myocardium was detected (Yasojima, K.; Schwab, C.; McGeer, E. G.; McGeer, P. L.; Circulation Research 83 (1998), 860-869). This was also detected in inflammatory disorders of the brain, e.g. multiple sclerosis and bacterial meningitis, and in colitis.
Evidence that complement activation has taken place can be provided by detecting the cell lysis complex in the tissue and by detecting soluble SC5b-9 or other activation products of complement, e.g. factor Bb, C3a; C4a, C5a; C3b, C3d; etc., in the plasma. By corresponding tests, it was possible to demonstrate, inter alia, participation of the complement system in the atherosclerosis as well as to show a relationship with myocardial infarction, unstable angina pectoris and organ transplantations, to mention but a few examples.
Raised blood levels of complement proteins, such as C3 or C4, are correlated with various cardiovascular disorders, e.g. heart failure, as well as diabetes. A similar relationship has imposulated for an increase in TNF in the case of heart failure. Initial studies on the treatment of heart failure with TNF inhibitors (soluble TNF receptor, antibodies) were rated positively. TNF is secreted, for example, after stimulation by complement factor C5a. It has been possible to show that inhibition of the C5a action prevents release of TNF (XVII International Complement Workshop, P. Ward, Abstract 324 in Molecular Immunology 35 (411 6-7), 1998). Accordingly, a treatment of disorders, in which raised levels of complement proteins are present, with the inhibitors described in this publication is possible, as the treatment of disorders in which raised levels of TNF are present.
Furthermore, the participation of complement has been demonstrated in the case of (Atherosclerosis 132 (1997); 131-138. Particular complications due to rapid atherosclerotic processes occur, for example, in organs after transplantations. These processes are the most frequent reason for the chronic fa
Haupt Andreas
Hillen Heinz
Kling Andreas
Mack Helmut
Schmidt Martin
BASF - Aktiengesellschaft
Lukton D.
Wood Phillips Katz Clark & Mortimer
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