Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-11-13
2004-02-17
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06693134
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to organic compounds acting as chemokine receptor ligands, including antagonists of CXC chemokine receptor-4 (CXCR-4) and therapeutic uses thereof, such as in the treatment of hematopoietic cells and in the treatment of chemokine or chemokine receptor mediated diseases.
BACKGROUND OF THE INVENTION
Cytokines are soluble proteins secreted by a variety of cells including monocytes or lymphocytes that regulate immune responses. Chemokines are chemotactic cytokines that belongs to a large family of chemoattractant molecules involved in the directed migration of immune cells. They regulate a variety of biological responses and promote the recruitment of multiple lineages of leukocytes and lymphocytes to a specific body organ tissues. The functional role generally assigned to chemokines in the immune process is to elicit mobilization of immune cells against pathogenic organisms by direct recruitment and activation. Based on their structural similarity, chemokines may be subdivided into four subfamilies, CXC, CC, C and CX
3
C, depending on the position of their first two cysteine residues. SDF-1 belongs to the CXC chemokine family. It exerts its biological activities by binding to a specific cell surface receptor, CXC Chemokine receptor 4 (CXCR-4). In human, CXC chemokine genes are clustered on chromosome 4 (with the exception of SDF-1 gene, which has been localized to chromosome 10) and CC chemokine genes are clustered on chromosome 17.
The molecular targets for chemokines are cell surface receptors CXCR-4, one such receptor is a G protein coupled 7 transmembrane protein, and was previously called LESTR. Majority of chemokine receptors identified to date bind several distinct chemokines at high affinity, with the exception of CXCR-4, which binds only SDF-1. SDF-1 is thought to be the natural ligand for CXCR-4. CXCR-4 is widely expressed on cells of hematopoietic origin, and is a major co-receptor with CD4
+
for human immunodeficiency virus 1 (HIV-1). CXCR-4 was found to be overexpressed in glioblastoma multiforme tumor tissue (GMTT), as compared to normal brain tissue (NBT). Expression analysis indicated that CXCR-4 is overexpressed in 57% of the primary glioblastoma tissues and in 8% of the glioblastoma cell lines. Gene-specific RT-PCR analysis indicated that the CXCR-4 gene is overexpressed in several malignant glioma tissues, breast tumor tissues and cell lines. Northern blot analysis indicated expression of CXCR-4 at high levels in certain leukemias, uterine cancer, and Burkitt's lymphoma cell lines. The occipital and temporal lobe showed high levels of CXCR-4 in normal human brain. In adult mouse, CXCR-4 is expressed only in brain, spinal cord, bone marrow, and pituitary gland. Antisense CXCR-4 overexpression in glioblastoma cells caused inhibition of cell proliferation and induction of cellular differentiation in vitro. These findings indicate that CXCR-4 expression may play an important role during embryonic development and also in the genesis of human gliomas; that CXCR-4 plays an important role in the tumorigenic properties of brain, breast, and other tumor types. Its unique expression during mouse development also indicates that CXCR-4 plays an important role in the normal function of brain, spinal cord, and bone marrow during development.
SDF-1 gene occurs in two alternative splicing variants, producing SDF-1 alpha and SDF-1 beta (together referred to herein as SDF-1). The native and genomic amino acid sequences of SDF-1 alpha and SDF-1 beta have been determined .
SDF-1 is functionally distinct from other chemokines in that it is reported to have a fundamental role in the trafficking, exporting and homing of bone marrow progenitor cells. It is also structurally distinct in that it has only about 22% amino acid sequence identity with other CXC chemokines. SDF-1 appears to be produced constitutively by several cell types, and particularly high levels are found in bone-marrow stromal cells. A basic physiological role for SDF-1 is implied by the high level of conservation of the SDF-1 sequence between species. In vitro, SDF-1 stimulates chemotaxis of a wide range of cells including monocytes and bone marrow derived progenitor cells. It also stimulates a high percentage of resting and activated T-lymphocytes.
Chemokines and their receptors determine the distribution of leukocytes within tissues both in healthy and disease states. CXCR-4 and its ligand SDF-1 are found to be involved in the perivascular accumulation of T cells in rheumatoid arthritis. Mast cells are generally considered to be less mobile, residing within tissue sites. However, mast cells increase during inflammation, and are recognized to be important in regulating local neutrophil infiltration. Stimulation of human mast cells with SDF-1 induces a significant increase in intracellular calcium levels. In vitro, SDF-1 mediates dose-dependent migration of human cord blood-derived mast cells and HMC-1 cells across HUVEC monolayer.
SDF-1 is a chemoattractant for CD34(+) progenitor cells, both in vitro and in vivo, and SDF-1 and CXCR-4 are involved in homing of progenitor cells to bone marrow. Experiments indicated that SDF-1 is involved in hematopoiesis, and promotion of the proliferation of human CD34(+) cells purified from normal adult peripheral blood (PB). When CXCR-4 was expressed on PB CD34(+) cells, the amount of CXCR-4 on PB CD34(+) cells was found to be 10 times higher when CD34(+) cells were purified following overnight incubation. CXCR-4 overexpression is correlated with a primitive PB CD34(+) cell subset defined by a CD34(high) CD38(low) CD71(low)c-Kit(low)Thy-1(+) antigenic profile. The functional significance of CXCR-4 expression was ascertained by the promoting effect of SDF-la on cell cycle, proliferation, and colony formation. SDF-1 alone increases the percentage of CD34(+) cells in the S+G(2)/M phases and sustains their survival. In synergy with cytokines, SDF-1 increases PB CD34(+) and CD34(high)CD38(low) cell expansion and colony formation.
A variety of diseases require treatment with agents, which are preferentially cytotoxic to dividing cells. Cancer cells, for example, may be targeted with cytotoxic doses of radiation or chemotherapeutic agents. A significant side-effect of cancer therapy is the pathological impact of such treatments on rapidly dividing normal cells. These normal cells may for example include hair follicles, mucosal cells and the hematopoietic cells, such as primitive bone marrow progenitor cells and stem cells.
Hematopoietic cells that are uncommitted to a final differentiated cell type are defined herein as “progenitor” cells. Hematopoietic progenitor cells possess the ability to differentiate into a variety of cell types directly or indirectly through a particular developmental lineage. Undifferentiated, pluripotent progenitor cells that are not committed to any lineage are referred to herein as “stem cells.” All hematopoietic cells can in theory be derived from a single stem cell, which is also able to perpetuate the stem cell lineage as daughter cells become differentiated.
Indiscriminating destruction of hematopoietic cells, such as stem, progenitor or precursor cells, can lead to a reduction in normal mature blood cell counts, such as leukocytes and red blood cells. A major impact on mature cell numbers may be seen particularly with neutrophils (neutropaenia) and platelets (thrombocytopenia), cells which naturally have relatively short half-lives. A decrease in leukocyte count, with concomitant loss of immune system function, may increase a patient's risk of opportunistic infection. Neutropaenia resulting from chemotherapy may for example occur within two or three days of cytotoxic treatments, and may leave the patient vulnerable to infection for up to 2 weeks until the hematopoietic system has recovered sufficiently to regenerate neutrophil counts. A reduced leukocyte count (leukopenia) as a result of cancer therapy may become sufficiently serious that therapy
Merzouk Ahmed
Salari Hassan
Saxena Geeta
Tudan Christopher R.
Bozicevic, Field & Francis
Chemokine Therapeutics Corporation
Field Bret E.
Reamer James H.
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