Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-26
2003-12-23
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S214000, C548S182000, C548S200000, C548S517000, C549S473000, C514S365000, C514S369000, C514S422000
Reexamination Certificate
active
06667318
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel compounds which bind CD11/CD18 adhesion receptors, in particular Lymphocyte Function-associated Antigen-1 (LFA-1) as well as pharmaceutical compositions containing these compounds which are useful for treating disorders mediated thereby.
BACKGROUND OF THE INVENTION
Inflammation
Human peripheral blood is composed principally of red blood cells, platelets and white blood cells or leukocytes. The family of leukocytes are further classified as neutrophils, lymphocytes (mostly B- and T-cell subtypes), monocytes, eosinophils and basophils. Neutrophils, eosinophils and basophils are sometimes referred to as “granulocytes” or “polymorphonuclear (PMN) granulocytes” because of the appearance of granules in their cytoplasm and their multiple nuclei. Granulocytes and monocytes are often classified as “phagocytes” because of their ability to phagocytose or ingest micro-organisms and foreign mater referred to generally as “antigens”. Monocytes are so called because of their large single nucleus and these cells may in turn become macrophages. Phagocytes are important in defending the host against a variety of infections and together with lymphocytes are also involved in inflammatory disorders. The neutrophil is the most common leukocyte found in human peripheral blood followed closely by the lymphocyte. In a microliter of normal human peripheral blood, there are about 6,000 leukocytes, of which about 4,000 are neutrophils, 1500 are lymphocytes, 250 are monocytes, 150 are eosinophils and 25 are basophils.
During an inflammatory response peripheral blood leukocytes are recruited to the site of inflammation or injury by a series of specific cellular interactions (see FIG. 1). The initiation and maintenance of immune functions are regulated by intercellular adhesive interactions as well as signal transduction resulting from interactions between leukocytes and other cells. Leukocyte adhesion to vascular endothelium and migration from the circulation to sites of inflammation is a critical step in the inflammatory response (FIG. 1). T-cell lymphocyte immune recognition requires the interaction of the T-cell receptor with antigen (in combination with the major histocompatibility complex) as well as adhesion receptors, which promote attachment of T-cells to antigen-presenting cells and transduce signals for T-cell activation. The lymphocyte function associated antigen-1 (LFA-1) has been identified as the major integrin that mediates lymphocyte adhesion and activation leading to a normal immune response, as well as several pathological states (Springer, T. A.,
Nature
346:425-434 (1990)). Intercellular adhesion molecules (ICAM)-1, -2, and -3, members of the immunoglobulin superfamily, are ligands for LFA-1 found on endothelium, leukocytes and other cell types. The binding of LFA-1 to ICAMs mediate a range of lymphocyte functions including lymphokine production of helper T-cells in response to antigen presenting cells, T-lymphocyte mediated target cells lysis, natural killing of tumor cells, and immunoglobulin production through T-cell-B-cell interactions. Thus, many facets of lymphocyte function involve the interaction of the LFA-1 integrin and its ICAM ligands. These LFA-1:ICAM mediated interactions have been directly implicated in numerous inflammatory disease states including; graft rejection, dermatitis, psoriasis, asthma and rheumatoid arthritis.
While LFA-1 (CD11a/CD18) on lymphocytes plays a key role in chronic inflammation and immune responses, other members of the leukocyte integrin family (CD11b/CD18, CD11c/CD18 and CD11d/CD18) also play important roles on other leukocytes, such as granulocytes and monocytes, particularly in early response to infective agents and in acute inflammatory response.
The primary function of polymorphonuclear leukocytes, derived from the neutrophil, eosinophil and basophil lineage, is to sense inflammatory stimuli and to emigrate across the endothelial barrier and carry out scavenger function as a first line of host defense. The integrin Mac-1(CD11b/CD18) is rapidly upregulated on these cells upon activation and binding to its multiple ligands which results in the release of oxygen derived free radicals, protease's and phospholipases. In certain chronic inflammatory states this recruitment is improperly regulated resulting in significant cellular and tissue injury. (Harlan, J. M.,
Acta Med Scand Suppl.,
715:123 (1987); Weiss, S.,
New England J. of Med.,
320:365 (1989)). LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) The (CD11/CD18) family of adhesion receptor molecules comprises four highly related cell surface glycoproteins; LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), p150.95 (CD11c/CD18) and (CD11d/CD18). LFA-1 is present on the surface of all mature leukocytes except a subset of macrophages and is considered the major lymphoid integrin. The expression of Mac-1, p150.95 and CD11d/CD18 is predominantly confined to cells of the myeloid lineage (which include neutrophils, monocytes, macrophage and mast cells). Functional studies have suggested that LFA-1 interacts with several ligands, including ICAM-1 (Rothleinet al.,
J. Immunol.
137:1270-1274 (1986), ICAM-2, (Staunton et al.,
Nature
339:361-364 (1989)), ICAM-3 (Fawcett et al.,
Nature
360:481-484 (1992); Vezeux et al.,
Nature
360:485-488, (1992); de Fougerolles and Springer,
J. Exp. Med.
175:185-190 (1990)) and Telencephalin (Tian et al.,
J. Immunol.
158:928-936 (1997)).
The CD11/CD18 family is related structurally and genetically to the larger integrin family of receptors that modulate cell adhesive interactions, which include; embryogenesis, adhesion to extracellular substrates, and cell differentiation (Hynes, R. O.,
Cell
48:549-554 (1987); Kishimotoet al.,
Adv. Immunol.
46:149-182 (1989); Kishimotoet al.,
Cell
48:681-690 (1987); Ruoslahtiet al., Science 238:491-497 (1987).
Integrins are a class of membrane-spanning heterodimers comprising an &agr; subunit in noncovalent association with a &bgr; subunit. The &bgr; subunits are generally capable of association with more than one &agr; subunit and the heterodimers sharing a common &bgr; subunit have been classified as subfamilies within the integrin population (Larson and Springer, “Structure and function of leukocyte integrins,”
Immunol. Rev
114:181-217 (1990)).
The integrin molecules of the CD11/CD18 family, and their cellular ligands, have been found to mediate a variety of cell—cell interactions, especially in inflammation. These proteins have been demonstrated to be critical for adhesive functions in the immune system (Kishimotoet al.,
Adv. Immunol.
46:149-182 (1989)). Monoclonal antibodies to LFA-1 have been shown to block leukocyte adhesion to endothelial cells (Dustin et al.,
J. Cell. Biol.
107:321-331 (1988); Smith et al.,
J. Clin. Invest.
83:2008-2017 (1989)) and to inhibit T-cell activation (Kuypers et al.,
Res. Immnunol.,
140:461 (1989)), conjugate formation required for antigen-specific CTL killing (Kishimotoet al.,
Adv. Immunol.
46:149-182 (1989)), T. cell proliferation (Davignonet al.,
J. Immunol.
127:590-595 (1981)) and NK cell killing (Krenskyet al.,
J. Immunol.
131:611-616 (1983)). ICAMs
ICAM-1 (CD54) is a cell surface adhesion receptor that is a member of the immunoglobulin protein super-family (Rothleinet al.,
J. Immunol.
137:1270-1274 (1986); Stauntonet al.,
Cell
52:925-933 (1988). Members of this superfamily are characterized by the presence of one or more Ig homology regions, each consisting of a disulfide-bridged loop that has a number of anti-parallel &bgr;-pleated strands arranged in two sheets. Three types of homology regions have been identified, each with a typical length and having a consensus sequence of amino acid residues located between the cysteines of the disulfide bond (Williams, A. F. et al.
Ann Rev. Immunol.
6:381-405 (1988); Hunkapillar, T. et al.
Adv. Immunol.
44:1-63 (1989). ICAM-1 is expressed on a variety of hematopoietic and non-hematopoietic cells and is upregulated at sites of inflammation by a variety of inflammatory med
Burdick Daniel J.
Gadek Thomas R.
Marsters James C.
Oare David
Reynolds Mark E.
Aulakh Charanjit S.
Evans David W
Genentech Inc.
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