Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-24
2004-06-15
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S152000, C544S180000, C544S183000, C544S194000, C544S235000, C544S236000, C544S256000, C544S279000, C544S349000, C544S353000, C514S314000
Reexamination Certificate
active
06750348
ABSTRACT:
TECHNICAL FIELD
This invention generally relates to novel compounds, pharmaceutical compositions and their use. This invention more specifically relates to novel heterocyclic compounds that bind to chemokine receptors, including CXCR4 and CCR5, and demonstrates protective effects against infection of target cells by a human immunodeficiency virus (HIV).
BACKGROUND OF THE INVENTION
Approximately 40 human chemokines have been described, that function, at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: P. Ponath,
Exp. Opin. Invest. Drugs
, 7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute a family of proteins, approximately 8-10 kDa in size. Chemokines appear to share a common structural motif, that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the “CC” or &bgr;-chemokines and the “CXC” or &agr;-chemokines. The receptors of these chemokines are classified based upon the chemokine that constitutes the receptor's natural ligand. Receptors of the &bgr;-chemokines are designated “CCR”; while those of the &agr;-chemokines are designated “CXCR”.
Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation. More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta et al.,
J. Biolog. Chem
., 7:4282-4287, 1998). Two specific chemokines have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
In most instances, HIV initially binds via its gp120 envelope protein to the CD4 receptor of the target cell. A conformational change appears to take place in the gp120 which results in its subsequent binding to a chemokine receptor, such as CCR-5 (Wyatt et al.,
Science
, 280:1884-1888 (1998)). HIV-1 isolates arising subsequently in the infection bind to the CXCR4 chemokine receptor. In view of the fact that the feline immunodeficiency virus, another related retrovirus, binds to a chemokine receptor without needing to bind first to the CD4 receptor, suggests that chemokine receptors may be the primordial obligate receptors for immunodeficiency retroviruses.
Following the initial binding by HIV to CD4, virus-cell fusion results, which is mediated by members of the chemokine receptor family, with different members serving as fusion cofactors for macrophage-tropic (M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carroll et al.,
Science
, 276: 273-276 1997). During the course of infection within a patient, it appears that a majority of HIV particles shift from the M-tropic to the more aggressive T-tropic viral phenotype (Miedema et al.,
Immune. Rev
., 140:35 (1994)) Curiously, the M-tropic viral phenotype correlates with the virus's ability to enter the cell following binding of the CCR-5 receptor, while the T-tropic viral phenotype correlates with viral entry into the cell following binding and membrane fusion with the CXCR-4 receptor. Clinically observations suggest that patients who possess genetic mutations in the CCR-5 or CXCR4 appear resistant or less susceptible to HIV infection.
However, the binding of chemokine receptors to their natural ligands appears to serve a more evolutionary and central role than only as mediators of HIV infection. The chemokine receptor, CXCR-4 has been found to be essential for the vascularization of the gastrointestinal tract (Tachibana et al.,
Nature
, 393:591-594 (1998)) as well as haematopoiesis and cerebellar development (Zou et al., Nature, 393:591-594 (1998)). Interference with any of these important functions served by the binding of pre-B-cell growth-stimulating factor/stromal derived factor (PBSF/SDF-1) to the CXCR-4 chemokine receptor results in lethal deficiencies in vascular development, haematopoiesis and cardiogenesis. Similarly, fetal cerebellar development appears to rely upon the effective functioning of CXCR-4 in neuronal cell migration and patterning in the central nervous system. This G-protein-coupled chemokine receptor appears to play a critical role in ensuring the necessary patterns of migration of granule cells in the cerebellar anlage.
In attempting to better understand the relationship between chemokines and their receptors, recent experiments to block the binding of HIV to the CXCR4 chemokine receptor were carried out through the use of monoclonal antibodies or small molecules that appear to suggest a useful therapeutic strategy (Schols et al,
J. Exp. Med
. 186:1383-1388 (1997); Schols et al.,
Antiviral Research
35:147-156 (1997)). Small molecules, such as bicyclams, appear to specifically interfere with the CXCR4 binding and not CCR-5 binding (Donzella et al,
Nature Medicine
, 4:72-77 (1998)). These experiments demonstrated interference with HIV entry and membrane fusion into the target cell in vitro. Additional experiments monitoring the calcium flux or Ca
2+
mobilization assay demonstrated that a bicyclam also functioned as an antagonist to signal transduction resulting from the binding of stromal derived factor or SDF-1&agr;, the natural chemokine to CXCR4. SDF-1 has been shown to be essential for CXCR4 dependent migration of human stem cell function in non-obese diabetic (NOD) severe combined immunodeficient (SCID) mice (Peled et al,
Science
283: 845-848 (1998)). The role of CXCR4 appears critical for migration to SDF-1 and localization of stem cells in bone marrow.
U.S. Pat. No. 5,583,131, U.S. Pat. No. 5,698,546 and U.S. Pat. No. 5,817,807, which are herein incorporated in their entirety by reference, disclose cyclic compounds that are active against HIV-1 and HIV-2 in in vitro tests. It was subsequently discovered and further disclosed in copending application U.S. Ser. No. 09/111,895 that these compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 receptor for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural CXC-chemokine for CXCR4, stromal cell-derived factor 1&agr; (SDF-1).
Additionally we have shown that these cyclic polyamine antiviral agents described in the above-mentioned patents have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
We further disclosed that these novel compounds demonstrate protective effects against HIV infection of target cells by binding in vitro to the CC-5 receptor (CCR-5).
Herein, we disclose novel compounds that exhibit protective effects against HIV infection of target cells by binding to chemokine receptors, including CXCR4 and CCR5, in a similar manner to the previously disclosed macrocyclic compounds. (see Table 1 for comparative examples).
SUMMARY OF THE INVENTION
The present invention provides novel compounds that bind chemokine receptors and interfere with the binding of the natural ligand thereto. The compounds of the present invention are useful as agents demonstrating protective effects on target cells from HIV infection. Other embodiments of the present invention are compounds that act as antagonists or agonists of chemokine receptors, which are useful as agents capable of reconstituting the immune system by increasing the level of CD4
+
cells; as antagonist agents of apoptosis in immune cells, such as CD8
+
cells, and neuronal cells; as antagonist agents of migration of huma
Atsma Bem
Bogucki David
Bridger Gary
Crawford Jason
Harwig Curtis
AnorMED Inc.
Balasubramanian Venkataraman
Morrison & Foerster / LLP
Raymond Richard L.
LandOfFree
Chemokine receptor binding heterocyclic compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Chemokine receptor binding heterocyclic compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chemokine receptor binding heterocyclic compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3362731