Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-27
2003-11-25
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S469000, C549S051000, C549S467000, C549S470000
Reexamination Certificate
active
06653340
ABSTRACT:
TECHNICAL FIELD
The present invention is concerned with new compounds, and particularly those having a fused bicyclic ring substituted with an amidine moiety. These compounds are each potent inhibitors of Factor D of the alternate pathway of complement, C1s of the classical pathway of complement, Factors Xa, XIIa, VIIa and thrombin of the coagulation pathway, plasmin in the fibrinolytic pathway, and kallikrein and high molecular weight kininogen in the inflammatory pathways. These proteases, which have serine in their active site, are called serine proteases and they are pivotal to most of the processes of inflammation and coagulation. In fact, these various systems are interactive with one another and it is difficult to activate one pathway without it influencing the others (see Diagram 1).
BACKGROUND OF INVENTION
Early in this century, it was noted that antibodies were not able to lyse bacteria by themselves. Factors were identified in serum which were required for the lysis of bacteria by antibodies. In 1989 Ehrlich and Morgenroth proposed the term “complements” for these factors because they complemented the activity of antibodies.
For many years cytolysis was the only known function of complement. During the past twenty five years, data in animals, including man, have identified the considerable biological potential of the complement system. The complement system functions as a “cascade.” Namely, once an activator of the system converts a zymogen to an active enzyme, the activated enzyme then activates one or more proteins at the next stage, which in turn activates other zymogens. This can lead to profound biological effects, if the system is not controlled. Normally, well-defined regulatory (inhibitory) mechanisms are in place to regulate complement activation. However, in a host of pathophysiological conditions, inappropriate activation of the complement system occurs, and cell damage and cytolysis occur in major organ systems. Inappropriate complement activation has been identified in preclinical and clinical models of a host of inflammatory diseases, including autoimmune diseases such as inflammatory arthritis, cerebral and cardiac ischemic insult, and adult respiratory distress syndrome, as a major pathophysiological pathway.
The complement system is composed of 20 plasma proteins that interact in a cascading series of enzymatic activations and feedback loops and provides an important effector mechanism for the humoral immune system. Activation of the complement system leads to induction of the inflammatory process, stimulation of phagocytosis, chemotaxis of white blood cells, release of inflammatory mediators from mast cells, increasing blood vessel permeability and ultimately the lysis and cell death of cancer cells, bacteria, and viral-infected cells and neutralization of viruses.
Complement proteins are produced by most cells in the body on a continual basis, and circulate through the blood in a non-activated form. Activation can be initiated by two pathways: the “classical” pathway and the “alternative” pathway. While both pathways end up with activation of the key component C3, each pathway plays a distinctive role in host defense. The components of each pathway participate in a cascade of limited proteolysis reactions, cleaving the inactive form of the next component into a minor fragment (which itself may have biological properties) and a major fragment that goes on to participate in the next reaction. The major fragments of the final five components form a “membrane attachment complex” (MAC) that lyses cell membranes.
The complement system has profound biological effects other than cell lysis. Most immune system effector cells have surface receptors for complement fragments. The complement fragments C3a, C4a and C5a induce inflammation and smooth muscle contraction and vasodilation. The binding of C3a, C4a or C5a to receptors on mast cells and basophils promotes the secretion of histamine and other mediators of inflammation. C5a also induces production of leukotrienes and affects neutrophils and monocytes in a variety of ways: increases adherence to endothelial cells, causes these cells to migrate toward the source of C5a, increases oxygen consumption and generation of free radicals and induces secretion of glycolytic and proteolytic enzymes. C5a also induces production of IL-1 by macrophages. C3a induces the release of granulocytes from bone marrow, leading to leukocytosis.
C3b and C4b act as opsonins, coating invading bacteria, parasites or other cells at the site of complement activation. This coating provides a recognition signal for phagocytic cells which then bind to and engulf the invading cells. Neutrophils, monocytes and eosinophils all have C3b receptors.
There are two mechanisms principally responsible for the inflammatory response and tissue destruction in autoimmune disease. In the first mechanisms, circulating autoantibodies bind to tissues carrying the antigen. The antigen-antibody complex on the tissue surface then triggers the classical pathway of complement and activates immune system cells that have Fc receptors. This in turn leads to cell lysis.
A second mechanism involves circulating immune complexes in the blood or intracellular fluids. The immune complexes are deposited in the kidneys, lungs, blood vessels and joints where they activate the complement cascade. Complement activation then leads to tissue destruction. This mechanism account for many of the serious complications of rheumatoid arthritis, systemic lupus, myasthenia gravis and autoimmune hemolytic anemia. In these diseases, immune complexes are continually being deposited and complement destruction of tissue is chronic. When the complexes deposit in joints, inflammation results and when they deposit in the kidney glomeruli complement activation destroys renal function.
Complement Factor D is a crucial enzyme in the alternative pathway of complement (see Volanakis, J. E., The complement system,
In Clinical Rheumatology
; Boll, G.; Koopman, W., Eds., W. B. Saunders: New York, 1986, pp. 21-27 and Volanakis, J. E., Narayana, S. V. L. Complement Factor D, a novel serine protease,
Protein Sci
. 1996, 5, p.553-564). Complement Factor D is essential for the formation and function of the C3- and C5-convertase of the alternative pathway of complement. Factor D is an enzyme necessary for the cleavage of C3b -bound factor B. It is a single polypeptide chain serine proteinase of Mr, 24,000. Human Factor D isolated from serum of normal individuals or from urine of patients with Fanconi's syndrome exhibits esterolytic activity against peptide thioester substrates.
The low esterolytic activity of purified Factor D is compatible with the apparent absence of a structural zymogen for the enzyme in blood. That “native” factor D in blood is in enzymatically active form was demonstrated by Lesavre and Muller-Eberhard, Mechanism of Action of Factor D of the Alternate Complement Pathway,
J. Exp. Med
., 148:1498-1509, 1978. They showed that distribution of Factor D hemolytic activity always overlapped that of antigenically measured Factor D protein when plasma or serum were subjected to various separation procedures. In addition, it has been shown that Factor D in serum can be inactivated by diisopropyl fluorophosphate and also by a series of serine proteinase inhibitors derived from isocoumarin. Inhibition of Factor D by these inhibitors results in inhibition of the alternative pathway indicating that no other proteinase can substitute for Factor D. Factor D was also shown to be synthesized and secreted in hemolytically active form by U937 cells, human blood-derived macrophages and HepG2 cells.
The serum concentration of Factor D, 1.8±0.4 ug/mL is the lowest of any complement protein. Studies on patients with renal insufficiency and in vivo microperfusion experiments using rat kidneys have indicated that the low concentration of Factor D is maintained by an extremely rapid catabolic rate. Due to its small size, Factor D is filtered through the glomerular membrane and is catabolized b
Babu Yarlagadda S.
Bennett J. Claude
Niwas Shri
Rowland R. Scott
BioCryst Pharmaceuticals Inc.
Connolly Bove & Lodge & Hutz LLP
Solola T. A.
LandOfFree
Compounds useful in the complement, coagulat and kallikrein... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds useful in the complement, coagulat and kallikrein..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds useful in the complement, coagulat and kallikrein... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3116140