Methods of treating C1s-mediated diseases and conditions and...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S438000

Reexamination Certificate

active

06492403

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of inhibiting the enzyme C1s, a protease in the classical pathway of the complement system, and the use of this inhibition to treat or ameliorate acute or chronic disorders in mammals.
2. Related Art
The immune system of the human body is equipped with several defense mechanisms to respond to bacterial, viral, or parasitic infection and injury. One such defense mechanism involves the complement system. Complement consists of a complex series of approximately 30 plasma and membrane protein components, many of which are proteinases. Once activated, this system of enzymes non-specifically complements the immunologically specific effects of antibody by modulating the immune response, lysing target cells, stimulating vascular and other smooth muscle cells, facilitating the transport of immune complexes, producing anaphylatoxins which cause degranulation of mast cells and release of histamine, stimulating chemotaxis (migration) of leukocytes towards the area of complement activity, activating B lymphocytes and macrophages, and inducing phagocytosis and lysis of cells (Eisen, H. N.,
Immunology
, Harper & Row Publishers, Inc. Hagerstown, Md., p. 512 (1974); Roitt, I. et al.,
Immunology
, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985); U.S. Pat. Nos. 5,472,939 and 5,268,363).
The complement system functions as a “cascade”. The enzyme cascades are initiated when inactive enzyme precursor molecules are activated, through limited proteolysis, by membrane-bound enzymes. A small fragment is lost from the enzyme precursor and a nascent membrane binding site is revealed. The major fragment then binds to the membrane as the next functionally active enzyme of the complement cascade. Since each enzyme is able to activate many enzyme precursors, the system forms an amplifying cascade, resembling the reactions seen in blood clotting and fibrinolysis (Roitt, I. et al.,
Immunology
, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985)).
The proteins of the complement system form two inter-related enzyme cascades, termed the classical and alternative pathways. The classical pathway is usually initiated by antigen-antibody complexes, while the alternative pathway is activated by specific polysaccharides, often found on bacterial, viral, and parasitic cell surfaces. The classical pathway consists of components C1-C9, while the alternative pathway consists of components C3 and several factors, such as Factor B, Factor D, and Factor H.
The sequence of events comprising the classical complement pathway consists of three stages: recognition, enzymatic activation, and membrane attack leading to cell death. The first phase of complement activation begins with C1. C1 is made up of three distinct proteins: a recognition subunit, C1q, and the serine proteinase subcomponents, C1r and C1s, which are bound together in a calcium-dependent tetrameric complex, C1r
2
s
2
. An intact C1 complex is necessary for physiological activation of C1 to result. Activation occurs when the intact C1 complex binds to immunoglobulin complexed with antigen. This binding activates C1s which then cleaves both the C4 and C2 proteins to generate C4a and C4b, as well as C2a and C2b. The C4b and C2a fragments combine to form the C3 convertase, which in turn cleaves C3 to form C3a and C3b (Makrides,
Pharmacol. Rev.
50:59-87 (1998); and U.S. Pat. No. 5,268,363). Both the classical and alternative pathways are capable of individually inducing the production of the C3 convertase to convert C3 to C3b, the generation of which is the central event of the complement pathway. C3b binds to C3b receptors present on neutrophils, eosinophils, monocytes and macrophages, thereby activating the terminal lytic complement sequence, C5-C9 (Roitt, I. et al.,
Immunology
, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985)).
Complement is designed to fight infection and injury; however, this same mechanism, if inappropriately activated, can cause a significant amount of inflammation, tissue damage, and other disease states such as the autoimmune diseases, as a result of the rapid and aggressive enzyme activity. Disease states implicating the complement system in inflammation and tissue damage include: the intestinal inflammation of Crohn's disease which is characterized by the lymphoid infiltration of mononuclear and polymorphonuclear leukocytes (Ahrenstedt et al.,
New Engl. J. Med.
322:1345-9 (1990)), thermal injury (burns, frostbite) (Gelfandetal,
J. Clin. Invest.
70:1170 (1982); Demling et al.,
Surgery
106:52-9(1989)), hemodialysis (Deppisch et al.,
Kidney Inst.
37:696-706 (1990); Kojima et al.,
Nippon Jenzo Gakkai Shi
31:91-7 (1989)), and post pump syndrome in cardiopulmonary bypass (Chenoweth et al.,
Complement. Inflamm.
3:152-165 (1981); Chenoweth et al.,
Complement
3:152-165 (1986); Salama et al.,
N. Engl. J. Med.
318:408-14 (1988)). Both complement and leukocytes are reported to be implicated in the pathogenesis of adult respiratory distress syndrome (Zilow et al.,
Clin. Exp. Immunol.
79:151-57 (1990); Langlois et al.,
Heart Lung
18:71-84 (1989)). Activation of the complement system is suggested to be involved in the development of fatal complication in sepsis (Hack et al.,
Am. J. Med.
86:20-26 (1989)) and causes tissue injury in animal models of autoimmune diseases such as immune-complex-induced vasculitis (Cochrane,
Springer Seminar Immunopathol.
7:263 (1984)), glomerulonephritis (Couser et al.,
Kidney Inst.
29:879 (1985)), hemolytic anemia (Schreiber & Frank,
J. Clin. Invest.
51:575 (1972)), myasthenia gravis (Lennon et al.,
J. Exp. Med.
147:973 (1978); Biesecker & Gomez,
J. Immunol.
142:2654 (1989)), type II collagen-induced arthritis (Watson & Townes,
J. Exp. Med.
162:1878 (1985)), and experimental allergic neuritis (Feasby et al.,
Brain Res.
419:97 (1987)). The complement system is also involved in hyperacute allograft and hyperacute xenograft rejection (Knechtle et al.,
J. Heart Transplant
4(5):541 (1985); Guttman,
Transplantation
17:383 (1974); Adachi et al.,
Trans. Proc.
19(1):1145 (1987)). Complement activation during immunotherapy with recombinant IL-2 appears to cause the severe toxicity and side effects observed from IL-2 treatment (Thijs et al.,
J. Immunol.
144:2419 (1990)).
Complement fragments generated by the classical portion of the complement cascade have been found to be present in the immune complexes formed against indigenous tissue in autoimmune diseases. Such diseases include, but are not limited to: Hashimoto's thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis (Biesecker et al.
J. Exp. Med.
154: 1779 (1981); Biesecker et al.,
N. Engl. J. Med.
306: 264 (1982); Falk et al.,
Clin. Research
32:503A (Abstract) (1984); Falk et al.,
J. Clin. Invest.
72:560 (1983); Dahl et al.,
J. Invest. Dermatol.
82:132 (1984); Dahl et al.,
Arch. Dermatol.
121:70 (1985); Sanders et al.,
Clin. Research
33:388A (Abstract) (1985); and U.S. Pat. Nos. 5,268,363 and 4,722,890).
Compounds that potently and selectively inhibit complement will have therapeutic applications in several acute and chronic immunological disorders, and a variety of neurodegenerative diseases. Evidence from both human and animal studies shows that activation of the classical complement pathway is primarily involved in neurodegenerative diseases of the central nervous system (CNS). Autoimmune diseases in which these inhibitors of the complement cascade system will be therapeutically useful include myasthenia gravis (MG), rheumatoid arthritis (in which the substance can be administered directly into a joint capsule to prevent complement activation), systemic lupus erythematosus. Neurodegenerativ

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